Substituted heterocyclic compounds for treating multidrug resistance

ABSTRACT

Substituted heterocyclic compounds are disclosed. The compounds are useful for treating multidrug resistance. The compounds can be formulated in compositions with a carrier and, optionally, a therapeutic agent. One suitable substituted heterocyclic compound has the formula:

CROSS REFERENCE TO PRIORITY APPLICATIONS

[0001] This is a divisional application of, and claims priority to,co-pending patent application Ser. No. 09/740,643, filed Dec. 19, 2000and Provisional Application Serial No. 60/241,127, filed Oct. 17, 2000.

FIELD OF THE INVENTION

[0002] This invention relates to compounds for treating multidrugresistance and methods for their preparation and use. More particularly,this invention relates to substituted heterocyclic compounds thatregulate the cellular transport proteins P-glycoprotein and MRP1, whichare the proteins believed to be largely responsible for causingmultidrug resistance in cancer patients.

BACKGROUND OF THE INVENTION

[0003] “Drug resistance” means a circumstance when a disease (e.g.,cancer) does not respond to a therapeutic agent. Drug resistance can beintrinsic, which means that the disease has never been responsive to thetherapeutic agent, or acquired, which means that the disease ceasesresponding to the agent or agents to which the disease had previouslybeen responsive. “Multidrug resistance” is a type of drug resistancewherein a disease is resistant to a variety of drugs that can befunctionally unrelated, structurally unrelated, or both. Multidrugresistance is a problem associated with cancer and other conditions,such as bacterial, viral, protozoal, and fungal diseases.

[0004] One cause of multidrug resistance in cancer patients is that manycancer cells express high levels of the transmembrane transportproteins, such as Pleiotropic-glycoprotein (also known as Pgp,P-glycoprotein, gp-170, or MDR1) and MRP1 (see Borst, P., “Multidrugresistance: A solvable problem?” Annals of Oncology, 10, suppl. 4, pp.S162-S164 (1999)). In adenosine-triphosphate driven processes, thesetransport proteins export hydrophobic compounds (such as vinblastine,daunorubicin, doxorubicin, etoposide, vincristine, and TAXOL®, which arecytotoxic drugs useful for treating cancer) from the cell in an effortto protect the cell from harm. The transport proteins remove thecompounds from the cell prior to their having a lethal effect on thecell (see Legrand, et. al, “Simultaneous Activity of MRP1 and Pgp IsCorrelated With In Vitro Resistance to Daunorubicin and With In VivoResistance in Adult Acute Myeloid Leukemia”, Blood, Vol. 94, No. 3, pp.1046-1056 (1999); and Zhu, B. T.; “A Novel Hypothesis for the Mechanismof Action of P-glycoprotein as a Multidrug Transporter,” MolecularCarcinogenesis 25, pp. 1-14 (1999)). Although it is not currently knownwhich of these two classes of proteins is more important for multidrugresistance, and indeed it may be that the class (or classes) of proteinwhich is important depends on the type of cancer and the particular drugor drugs used to treat the cancer, Pgp is known to be highly expressedin approximately 50% of human cancers which require drug therapy.Consequently, Pgp is believed to be a major cause of multidrugresistance.

[0005] Other types of multidrug resistance, such as antibacterial,antiviral, and antifungal multidrug resistance may also be caused by theaction of transport proteins that are similar to Pgp, and others (see“Annual Reports on Medicinal Chemistry—33; Section III Cancer andInfectious Diseases” ed. Plattner, J., Academic Press, Ch. 12, pp.121-130 (1998)).

[0006] Furthermore, Pgp is also expressed at high levels in thegastrointestinal tract, liver, kidneys, and brain, and therefore Pgprepresents a major pharmacological barrier to the bioavailability ofmany drugs (see Amudkar, et. al in “Biochemical, Cellular, andPharmacological Aspects of the Multidrug Transporter,” Annu. Rev.Pharmacol. Toxicol., 39, pp. 361-398 (1999)). For example, the oralbioavailability of many nutrients and drugs is negatively affected bythe action of Pgp present in the gastrointestinal tract. “Oralbioavailability” means the ability of a drug or nutrient that isadministered orally to be transported across the gastrointestinal tractand enter into the bloodstream. In addition, penetration of many drugsthrough the blood-brain barrier is adversely affected by Pgp.

SUMMARY OF THE INVENTION

[0007] This invention relates to novel compounds useful in treating orpreventing multidrug resistance (“MDR”). More specifically, thesecompounds are useful in treating or preventing P-glycoprotein-mediatedMDR and MRP1-mediated MDR. This invention further relates tocompositions comprising these compounds. This invention further relatesto methods for the preparation and use of the compounds andcompositions. The compounds and compositions of this invention are wellsuited for treatment of multidrug resistant cells, for prevention of thedevelopment of multidrug resistance, and for use in multidrug resistantchemotherapies.

DETAILED DESCRIPTION OF THE INVENTION

[0008] Publications and patents are referred to throughout thisdisclosure. All U.S. Patents cited herein are hereby incorporated byreference.

[0009] All percentages, ratios, and proportions used herein are byweight unless otherwise specified.

Definitions and Usage of Terms

[0010] The following is a list of definitions, as used herein.

[0011] “Aromatic group” means a group having a monocyclic or polycyclicring structure. Monocyclic aromatic groups contain 4 to 10 carbon atoms,preferably 4 to 7 carbon atoms, and more preferably 4 to 6 carbon atomsin the ring. Preferred polycyclic ring structures have two or threerings. Polycyclic structures having two rings typically have 8 to 12carbon atoms, preferably 8 to 10 carbon atoms in the rings. Polycyclicaromatic groups include groups wherein at least one, but not all, of therings are aromatic.

[0012] “Carbocyclic group” means a saturated or unsaturated hydrocarbonring. Carbocyclic groups are not aromatic. Carbocyclic groups aremonocyclic or polycyclic. Polycyclic carbocyclic groups can be fused,spiro, or bridged ring systems. Monocyclic carbocyclic groups contain 4to 10 carbon atoms, preferably 4 to 7 carbon atoms, and more preferably5 to 6 carbon atoms in the ring. Bicyclic carbocyclic groups contain 8to 12 carbon atoms, preferably 9 to 10 carbon atoms in the rings.

[0013] “Carrier” means one or more substances that are suitable foradministration to a subject (i.e., mammal) and that can be combined withthe active compound according to this invention. Carrier includes solidand liquid diluents, hydrotropes, surface-active agents, andencapsulating substances.

[0014] “Chemosensitizing agent” means a noncytotoxic compound thatsensitizes drug resistant cells to the action of cytotoxic drugs. Asused in this application, the term “chemosensitizing agent”, excludesthe active compounds of this invention.

[0015] “Halogen atom” means F, Cl, Br, or I.

[0016] “Heteroaromatic group” means an aromatic group containing carbonand 1 to 4 heteroatoms in the ring. Monocyclic heteroaromatic groupscontain 4 to 10 member atoms, preferably 4 to 7 member atoms, and morepreferably 4 to 6 member atoms in the ring. Preferred polycyclic ringstructures have two or three rings. Polycyclic structures having tworings typically have 8 to 12 member atoms, preferably 8 to 10 memberatoms in the rings. Polycyclic heteroaromatic groups include groupswherein at least one, but not all, of the rings are heteroaromatic.

[0017] “Heteroatom” means an atom other than carbon e.g., in the ring ofa heterocyclic group or the chain of a heterogeneous group. Preferably,heteroatoms are selected from the group consisting of sulfur,phosphorous, nitrogen and oxygen atoms. Groups containing more than oneheteroatom may contain different heteroatoms.

[0018] “Heterocyclic group” means a saturated or unsaturated ringstructure containing carbon atoms and 1 or more heteroatoms in the ring.Heterocyclic groups are not aromatic. Heterocyclic groups are monocyclicor polycyclic. Polycyclic heteroaromatic groups can be fused, spiro, orbridged ring systems. Monocyclic heterocyclic groups contain 4 to 10member atoms (i.e., including both carbon atoms and at least 1heteroatom), preferably 4 to 7, and more preferably 5 to 6 in the ring.Bicyclic heterocyclic groups contain 8 to 18 member atoms, preferably 9or 10 in the rings.

[0019] “Heterogeneous group” means a saturated or unsaturated chain ofnon-hydrogen member atoms comprising carbon atoms and at least oneheteroatom. Heterogeneous groups typically have 1 to 25 member atoms.Preferably, the chain contains 1 to 12 member atoms, more preferably 1to 10, and most preferably 1 to 6. The chain may be linear or branched.Preferred branched heterogeneous groups have one or two branches,preferably one branch. Preferred heterogeneous groups are saturated.Unsaturated heterogeneous groups have one or more double bonds, one ormore triple bonds, or both. Preferred unsaturated heterogeneous groupshave one or two double bonds or one triple bond. More preferably, theunsaturated heterogeneous group has one double bond.

[0020] “Hydrocarbon group” means a chain of 1 to 25 carbon atoms,preferably 1 to 12 carbon atoms, more preferably 1 to 10 carbon atoms,and most preferably 1 to 8 carbon atoms. Hydrocarbon groups may have alinear or branched chain structure. Preferred hydrocarbon groups haveone or two branches, preferably 1 branch. Preferred hydrocarbon groupsare saturated. Unsaturated hydrocarbon groups have one or more doublebonds, one or more triple bonds, or combinations thereof. Preferredunsaturated hydrocarbon groups have one or two double bonds or onetriple bond; more preferred unsaturated hydrocarbon groups have onedouble bond.

[0021] “IC₅₀” means concentration of drug required to produce a 50%inhibition of growth of cancer cells or 50% inhibition of activity.

[0022] “MDR” means multidrug resistance.

[0023] “Parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques.

[0024] “Pgp” means P-glycoprotein.

[0025] “Pharmaceutically acceptable” means suitable for use in a humanor other mammal.

[0026] “Protecting group” is a group that replaces the active hydrogenof a —OH, —COOH, or —NH₂ moiety thus preventing undesired side reactionat the moiety. Use of protecting groups in organic synthesis is wellknown in the art. Examples of protecting groups are found in ProtectingGroups in Organic Synthesis by Greene, T. W. and Wuts, P. G. M., 2nded., Wiley & Sons, Inc., 1991. Preferred protecting groups for hydroxylmoieties include silyl ethers, alkoxymethyl ethers, tetrahydropyranyl,tetrahydrofuranyl, esters, and substituted or unsubstituted benzylethers. Other preferred protecting groups include carbamates.

[0027] “Subject” means a living vertebrate animal such as a mammal(preferably human).

[0028] “Substituted aromatic group” means an aromatic group wherein 1 ormore of the hydrogen atoms bonded to carbon atoms in the ring have beenreplaced with other substituents. Preferred substituents includehydrocarbon groups such as methyl groups and heterogeneous groupsincluding alkoxy groups such as methoxy groups. The substituents may besubstituted at the ortho, meta, or para position on the ring, or anycombination thereof.

[0029] “Substituted carbocyclic group” means a carbocyclic group wherein1 or more hydrogen atoms bonded to carbon atoms in the ring have beenreplaced with other substituents. Preferred substituents includehydrocarbon groups such as alkyl groups (e.g, methyl groups) andheterogeneous groups such as alkoxy groups (e.g., methoxy groups).

[0030] “Substituted heteroaromatic group” means a heteroaromatic groupwherein 1 or more hydrogen atoms bonded to carbon atoms in the ring havebeen replaced with other substituents. Preferred substituents includemonovalent hydrocarbon groups including alkyl groups such as methylgroups and monovalent heterogeneous groups including alkoxy groups suchas methoxy groups.

[0031] “Substituted heterocyclic group” means a heterocyclic groupwherein 1 or more hydrogen atoms bonded to carbon atoms in the ring havebeen replaced with other substituents. Preferred substituents includemonovalent hydrocarbon groups including alkyl groups such as methylgroups and monovalent heterogeneous groups including alkoxy groups suchas methoxy groups. Substituted heterocyclic groups are not aromatic.

[0032] “Substituted heterogeneous group” means a heterogeneous group,wherein 1 or more of the hydrogen atoms bonded to carbon atoms in thechain have been replaced with other substituents. Preferred substituentsinclude monovalent hydrocarbon groups including alkyl groups such asmethyl groups and monovalent heterogeneous groups including alkoxygroups such as methoxy groups.

[0033] “Substituted hydrocarbon group” means a hydrocarbon group wherein1 or more of the hydrogen atoms bonded to carbon atoms in the chain havebeen replaced with other substituents. Preferred substituents includemonovalent aromatic groups, monovalent substituted aromatic groups,monovalent hydrocarbon groups including alkyl groups such as methylgroups, monovalent substituted hydrocarbon groups such as benzyl, andmonovalent heterogeneous groups including alkoxy groups such as methoxygroups.

[0034] “Substrate potential” means the likelihood that a compound foruse in treating multidrug resistance will be transported out of a cellby cellular transport proteins before effectively preventing orreversing multidrug resistance.

[0035] “Transport protein” means a protein that acts to remove cytotoxicsubstances from cells through the cell membrane. Transport proteinincludes P-glycoprotein, MRP1, and others.

[0036] “Treating multidrug resistance” means preventing multidrugresistance from developing in nonresistant cells, increasing orrestoring sensitivity of multidrug resistant cells to therapeutic orprophylactic agents, or both.

[0037] “Treating” means 1) preventing a disease (i.e., causing theclinical symptoms of the disease not to develop), 2) inhibiting thedisease (i.e., arresting the development of clinical symptoms of thedisease), 3) relieving the disease (i.e., causing regression of theclinical symptoms), and combinations thereof.

[0038] “Wax” means a lower-melting organic mixture or compound of highmolecular weight, solid at room temperature and generally similar informulation to fats and oils except that they contain no glycerides.

Active Compounds Used in this Invention

[0039] The active compounds of this invention are heterocycliccompounds. The active compounds have the general structure:

[0040] Groups A¹ and A² are each independently selected from the groupconsisting of a hydrogen atom and a group of the formula

[0041] with the proviso that A¹ and A² are not both hydrogen atoms and

denotes a point of attachment.

[0042] Each R¹ is independently selected from the group consisting of ahydrogen atom, a hydroxyl group, a hydrocarbon group, a substitutedhydrocarbon group, a heterogeneous group, a substituted heterogeneousgroup, a carbocyclic group, a substituted carbocyclic group, aheterocyclic group, a substituted heterocyclic group, an aromatic group,a substituted aromatic group, a heteroaromatic group, and a substitutedheteroaromatic group. R¹ is preferably a hydrogen atom or a hydroxylgroup. In group A¹, R¹ is preferably a hydrogen atom.

[0043] The subscript x is 0 to about 10, preferably 0 to about 1.

[0044] R² is selected from the group consisting of a hydrocarbon group,a substituted hydrocarbon group, a heterogeneous group, a substitutedheterogeneous group, a carbocyclic group, a substituted carbocyclicgroup, a heterocyclic group, a substituted heterocyclic group, anaromatic group, a substituted aromatic group, a heteroaromatic group,and a substituted heteroaromatic group. R² is preferably selected fromthe group consisting of a hydrocarbon group, a substituted hydrocarbongroup, a heterogeneous group, a substituted heterogeneous group, anaromatic group, a substituted aromatic group, a heteroaromatic group,and a substituted heteroaromatic group. More preferably, R² is asubstituted hydrocarbon group or a substituted heterogeneous group,wherein said group is substituted with a group selected from the groupconsisting of an aromatic group, a substituted aromatic group, aheteroaromatic group, and a substituted heteroaromatic group.

[0045] In a preferred embodiment of the invention, R² is selected fromthe group consisting of:

[0046] wherein a is at least about 2, b is at least about 2, c is about1 to about 3, and d is about 1 to about 3. Preferably, a and b are eachabout 3 to about 10. More preferably, a and b are each about 3.

[0047] R¹² and R¹³ are each independently selected from the groupconsisting of hydrocarbon groups and substituted hydrocarbon groups.Preferably, R¹² and R¹³ are substituted hydrocarbon groups such asalkoxy groups. Preferred alkoxy groups include methoxy, ethoxy, propoxy,and butoxy.

[0048] Each R¹⁴ is independently selected from the group consisting ofCH and a heteroatom. Preferably, the heteroatom is nitrogen. Morepreferably, each R¹⁴ is CH.

[0049] Groups D¹ and D² are each independently selected from the groupconsisting of —C(O)—and —NR³—,

[0050] wherein R³ is selected from the group consisting of a hydrogenatom and R², and with the proviso that optionally, R² and R³ may bebonded together to form a ring structure selected from the groupconsisting of heterocyclic groups and substituted heterocyclic groupswhen D² is —NR³—;

[0051] y is 0 or and z is 0 or 1,

[0052] with the provisos that when y is 0, z is 1 and when y is 1, z is0,

[0053] when y is 0 and D¹ is —NR³—, then D² is —C(O)—, and

[0054] when y is 0 and D² is —NR³—, then D¹ is —C(O)—.

[0055] Preferably, y is 0 and z is 1.

[0056] In one embodiment of the invention, R² and R³ are bonded togetherand the ring structure has 5 to 6 members. Preferably, the ringstructure formed by R² and R³ is a substituted heterocyclic group,wherein the substituted heterocyclic group is substituted with a groupselected from the group consisting of an aromatic group; a substitutedaromatic group; a heteroaromatic group; a substituted heteroaromaticgroup; a substituted hydrocarbon group, wherein the substitutedhydrocarbon group is substituted with a group selected from the groupconsisting of an aromatic group, a substituted aromatic group, aheteroaromatic group, and a substituted heteroaromatic group; and asubstituted heterogeneous group, wherein the substituted heterogeneousgroup is substituted with a group selected from the group consisting ofan aromatic group, a substituted aromatic group, a heteroaromatic group,and a substituted heteroaromatic group.

[0057] In a preferred embodiment of the invention, D¹ is —C(O)— and D²is —NR³—. In this embodiment, preferably R³ is selected from the groupconsisting of a hydrogen atom and a hydrocarbon group.

[0058] In an alternative embodiment of the invention, D¹ is —C(O)—, y is1, and z is 0.

[0059] In an alternative embodiment of the invention, D¹ is —NR³— and D²is —C(O)—. In this embodiment, preferably R³ is selected from the groupconsisting of a hydrogen atom and a hydrocarbon group.

[0060] A³ has the formula

[0061] wherein t is 0 to about 6, preferably 0 to about 2.

[0062] Group D⁴ is selected from the group consisting of —C(O)— and—CH(R¹)—. D⁴ is preferably—CH(R¹)—.

[0063] Group D⁵ is selected from the group consisting of —NR⁶(R⁷),—O_(r)R⁶, and —C(O)R⁶,

[0064] wherein r is 0 or 1, preferably 1;

[0065] R⁶ is selected from the group consisting of a hydrocarbon group,a substituted hydrocarbon group, a heterogeneous group, a substitutedheterogeneous group, a carbocyclic group, a substituted carbocyclicgroup, a heterocyclic group, a substituted heterocyclic group, anaromatic group, a substituted aromatic group, a heteroaromatic group,and a substituted heteroaromatic group; and

[0066] R⁷ is selected from the group consisting of a hydrogen atom andR⁶. R⁷ is preferably a hydrogen atom.

[0067] D⁵ is preferably —O_(r)R⁶, and R⁶ is preferably selected from thegroup consisting of an aromatic group, a substituted aromatic group, aheteroaromatic group, and a substituted heteroaromatic group. R⁶ is morepreferably selected from the group consisting of a heteroaromatic groupand a substituted heteroaromatic group. R⁶ is most preferably aheteroaromatic group. Preferred heteroaromatic groups for R⁶ have theformula:

[0068] wherein each X is independently selected from the groupconsisting of CH and a heteroatom, with the proviso that at least one Xis a heteroatom. The heteroatom is preferably nitrogen. Preferably, oneX is a heteroatom. Examples of heteroaromatic groups for X includequinolyl and isoquinolyl groups. Preferred quinolyl groups for X include4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, and 8-quinolyl. Morepreferably, X is 5-quinolyl.

[0069] In a preferred embodiment of the invention, D⁴ is —C(O)—, t is 0,and D⁵ is —C(O)R⁶.

[0070] In an alternative preferred embodiment of the invention, D⁴ is—C(O)— and D⁵ is —O_(r)R⁶.

[0071] In an alternative preferred embodiment of the invention, D⁴ is—CH(R¹)— and D⁵ is —O_(r)R⁶.

[0072] In an alternative preferred embodiment of the invention, D⁴ is—CH(R¹)- and D⁵ is —NR⁶(R⁷).

[0073] In an alternative preferred embodiment of the invention, D⁴ is—C(O)— and D⁵ is —NR⁶(R⁷).

[0074] Group A⁴ is a heterocyclic group having 4 to 9 member atoms.Preferably, A⁴ has 4 to 6 member atoms, most preferably 5 or 6 memberatoms.

[0075] Alternatively, the compound may be an optical isomer, adiastereomer, an enantiomer, a pharmaceutically-acceptable salt, abiohydrolyzable amide, a biohydrolyzable ester, and a biohydrolyzableimide of the structure, or combinations thereof.

[0076] Examples of compounds having the structure above are shown inTable 1. TABLE 1 Example Compounds

[0077] In Table 1 “Me” represents a methyl group.

[0078] The active compound of this invention inhibits at least onetransport protein. The active compound preferably inhibits Pgp or MRP1.More preferably, the active compound inhibits both Pgp and MRP1. In apreferred embodiment of this invention, the active compound inhibits Pgpand has low substrate potential for Pgp. In an alternative preferredembodiment, the active compound inhibits MRP1 and has low substratepotential for MRP1. In the most preferred embodiment of this invention,the active compound inhibits both Pgp and MRP1 and the active compoundhas low substrate potential for both Pgp and MRP1.

[0079] The degree to which a compound inhibits a transport protein canbe measured by quantitating the effectiveness of the compound towardrestoring drug sensitivity to multidrug resistant cells. Methods forquantitating the effectiveness of the active compounds toward restoringdrug sensitivity are readily available to one skilled in the art withoutundue experimentation (see U.S. Pat. Nos. 5,935,954 and 5,272,159, whichare hereby incorporated by reference for the purpose of disclosing thesemethods). Any assay known to measure the restoration of theanti-proliferative activity of a drug may be employed to test thecompounds of this invention. These assays use cell lines resistant toparticular drugs, and characterized by the presence of one or both ofPgp and MRP1. These cell lines include L1210, HL60, P388, CHO, and MCF7.Alternatively, resistant cell lines can be developed by methods readilyavailable to one of ordinary skill in the art without undueexperimentation (see Chaudhary, et al., “Induction of MultidrugResistance in Human Cells by Transient Exposure to DifferentChemotherapeutic Agents,” Journal of the National Cancer Institute, Vol.85, No. 8, pp. 632-639 (1993)). The cell line is then exposed tocompounds of this invention in the presence or absence of the drug towhich it is resistant, such as TAXOL®. The viability of the cellstreated with both the active compound and the drug can then be comparedto the viability of the cells treated only with the drug.

[0080] The active compound preferably also has low substrate potentialfor Pgp or MRP1. More preferably, the active compound has low substratepotential for both Pgp and MRP1. Substrate potential for a transportprotein can be determined by using an assay for measuring ATPaseactivity of the Pgp or MRP1 pumps (see, for example, Reference Example4, below).

[0081] Methods for quantitating accumulation of the active compounds arereadily available to one skilled in the art without undueexperimentation (see U.S. Pat. No. 5,272,159 which is herebyincorporated by reference for the purpose of disclosing assays forquantitating accumulation). These assays use cell lines resistant toparticular chemotherapeutic agents, and characterized by the presence ofone or both of Pgp and MRP1. The cell line is exposed to a labeled formof the active compound (e.g., radioactivity or fluorescence labeling)and the accumulation of the active compound is monitored over time. Theamount of active compound accumulated in the cell can be compared with acompound which is readily transported by these proteins, e.g. labeledTAXOL®.

Compositions of this Invention

[0082] This invention further relates to a composition. The compositioncan be used for treating various conditions or disease states. Thecomposition is preferably a pharmaceutical composition administered fortreatment or prevention of multidrug resistance. Standard pharmaceuticalformulation techniques are used, such as those disclosed in Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa. (1990) andU.S. Pat. No. 5,091,187, which is hereby incorporated by reference.

[0083] The composition comprises component (A) the active compounddescribed above and component (B) a carrier. The composition may furthercomprise component (C) an optional ingredient, such as a therapeuticagent.

[0084] Component (B) is a carrier. A carrier is one or more compatiblesubstances that are suitable for administration to a mammal.“Compatible” means that the components of the composition are capable ofbeing commingled with component (A), and with each other, in a mannersuch that there is no interaction which would substantially reduce theefficacy of the composition under ordinary use situations. Carriers mustbe of sufficiently high purity and sufficiently low toxicity to renderthem suitable for administration to the mammal being treated. Thecarrier can be inert, or it can possess pharmaceutical benefits,cosmetic benefits, or both, depending on the intended use as describedherein.

[0085] The choice of carrier for component (B) depends on the route bywhich component (A) will be administered and the form of thecomposition. The composition may be in a variety of forms, suitable, forexample, for systemic administration (e.g., oral, rectal, nasal,sublingual, buccal, or parenteral) or topical administration (e.g.,local application on the skin, ocular, liposome delivery systems, oriontophoresis).

Systemic Compositions

[0086] Carriers for systemic administration typically comprise one ormore ingredients selected from the group consisting of a) diluents, b)lubricants, c) binders, d) disintegrants, e) colorants, f) flavors, g)sweeteners, h) antioxidants, j) preservatives, k) glidants, m) solvents,n) suspending agents, o) surfactants, combinations thereof, and others.

[0087] Ingredient a) is a diluent. Suitable diluents include sugars suchas glucose, lactose, dextrose, and sucrose; polyols such as propyleneglycol; calcium carbonate; sodium carbonate; glycerin; mannitol;sorbitol; and maltodextrin. The amount of ingredient a) in thecomposition is typically about 1 to about 99%.

[0088] Ingredient b) is a lubricant. Suitable lubricants are exemplifiedby solid lubricants including silica, talc, stearic acid and itsmagnesium salts and calcium salts, calcium sulfate; and liquidlubricants such as polyethylene glycol and vegetable oils such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil, and oil oftheobroma. The amount of ingredient b) in the composition is typicallyabout 1 to about 99%.

[0089] Ingredient c) is a binder. Suitable binders includepolyvinylpyrrolidone; magnesium aluminum silicate; starches such as cornstarch and potato starch; gelatin; tragacanth; and cellulose and itsderivatives, such as sodium carboxymethylcellulose, ethylcellulose,methylcellulose, microcrystalline cellulose, andhydroxypropylmethylcellulose; carbomer; providone; acacia; guar gum; andxanthan gum. The amount of ingredient c) in the composition is typicallyabout 1 to about 99%.

[0090] Ingredient d) is a disintegrant. Suitable disintegrants includeagar, alginic acid and the sodium salt thereof, effervescent mixtures,croscarmelose, crospovidone, sodium carboxymethyl starch, sodium starchglycolate, clays, and ion exchange resins. The amount of ingredient d)in the composition is typically about 1 to about 99%.

[0091] Ingredient e) is a colorant such as an FD&C dye. The amount ofingredient e) in the composition is typically about 1 to about 99%.

[0092] Ingredient f) is a flavor such as menthol, peppermint, and fruitflavors. The amount of ingredient f) in the composition is typicallyabout 1 to about 99%.

[0093] Ingredient g) is a sweetener such as saccharin and aspartame. Theamount of ingredient g) in the composition is typically about 1 to about99%.

[0094] Ingredient h) is an antioxidant such as butylated hydroxyanisole,butylated hydroxytoluene, and vitamin E. The amount of ingredient h) inthe composition is typically about 1 to about 99%.

[0095] Ingredient j) is a preservative such as phenol, alkyl esters ofparahydroxybenzoic acid, benzoic acid and the salts thereof, boric acidand the salts thereof, sorbic acid and the salts thereof, chorbutanol,benzyl alcohol, thimerosal, phenylmercuric acetate and nitrate,nitromersol, benzalkonium chloride, cetylpyridinium chloride, methylparaben, ethyl paraben, and propyl paraben. Particularly preferred arethe salts of benzoic acid, cetylpyridinium chloride, methyl paraben andpropyl paraben, and sodium benzoate. The amount of ingredient j) in thecomposition is typically about 1 to about 99%.

[0096] Ingredient k) is a glidant such as silicon dioxide. The amount ofingredient k) in the composition is typically about 1 to about 99%.

[0097] Ingredient m) is a solvent, such as water, isotonic saline, ethyloleate, alcohols such as ethanol, glycerin, cremaphor, glycols (e.g.,polypropylene glycol and polyethylene glycol), and buffer solutions(e.g., phosphate, potassium acetate, boric carbonic, phosphoric,succinic, malic, tartaric, citric, acetic, benzoic, lactic, glyceric,gluconic, glutaric, and glutamic). The amount of ingredient m) in thecomposition is typically about 1 to about 99%.

[0098] Ingredient n) is a suspending agent. Suitable suspending agentsinclude AVICEL® RC-591 from FMC Corporation of Philadelphia, Pa. andsodium alginate. The amount of ingredient n) in the composition istypically about 1 to about 99%.

[0099] Ingredient o) is a surfactant such as lecithin, polysorbate 80,sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters,polyoxyethylene monoalkyl ethers, sucrose monoesters, lanolin esters,and lanolin ethers. Suitable surfactants are known in the art andcommercially available, e.g., the TWEENS® from Atlas Powder Company ofWilmington, Del. Suitable surfactants are disclosed in the C.T.F.A.Cosmetic Ingredient Handbook, pp.587-592 (1992); Remington'sPharmaceutical Sciences, 15th Ed., pp. 335-337 (1975); and McCutcheon'sVolume 1, Emulsifiers & Detergents, North American Edition, pp. 236-239(1994). The amount of ingredient o) in the composition is typicallyabout 1 to about 99%.

[0100] The carrier ingredients discussed above are exemplary and notlimiting. One skilled in the art would recognize that different carrieringredients may be added to or substituted for the carrier ingredientsabove. One skilled in the art would be able to select appropriatecarrier ingredients for systemic compositions without undueexperimentation.

[0101] Compositions for parenteral administration typically comprise (A)about 0.1 to about 10% of an active compound and (B) about 90 to about99.9% of a carrier comprising a) a diluent and m) a solvent. Preferably,component a) is propylene glycol and m) is selected from the groupconsisting of ethanol, ethyl oleate, water, isotonic saline, andcombinations thereof.

[0102] Compositions for oral administration can have various dosageforms. For example, solid forms include tablets, capsules, granules, andbulk powders. These oral dosage forms comprise a safe and effectiveamount, usually at least about 1%, and preferably from about 5% to about50%, of component (A). The oral dosage compositions further comprise (B)about 50 to about 99% of a carrier, preferably about 50 to about 95%.

[0103] Tablets can be compressed, tablet triturates, enteric-coated,sugar-coated, film-coated, or multiple-compressed. Tablets typicallycomprise (A) the active compound, and (B) a carrier comprisingingredients selected from the group consisting of a) diluents, b)lubricants, c) binders, d) disintegrants, e) colorants, f) flavors, g)sweeteners, k) glidants, and combinations thereof. Preferred diluentsinclude calcium carbonate, sodium carbonate, mannitol, lactose, andsucrose. Preferred binders include starch, and gelatin. Preferreddisintegrants include alginic acid, and croscarmelose. Preferredlubricants include magnesium stearate, stearic acid, and talc. Preferredcolorants are the FD&C dyes, which can be added for appearance. Chewabletablets preferably contain g) sweeteners such as aspartame and saccharinor f) flavors such as menthol, peppermint, and fruit flavors, or both.

[0104] Capsules (including time release and sustained releasecompositions) typically comprise (A) the active compound and (B) thecarrier comprising one or more a) diluents disclosed above in a capsulecomprising gelatin. Granules typically comprise (A) the active compound,and preferably further comprise k) glidants such as silicon dioxide toimprove flow characteristics.

[0105] The selection of ingredients in the carrier for oral compositionsdepends on secondary considerations like taste, cost, and shelfstability, which are not critical for the purposes of this invention.One skilled in the art can optimize appropriate ingredients withoutundue experimentation.

[0106] The solid compositions may also be coated by conventionalmethods, typically with pH or time-dependent coatings, such thatcomponent (A) is released in the gastrointestinal tract at various timesto extend the desired action. The coatings typically comprise one ormore components selected from the group consisting of cellulose acetatephthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulosephthalate, ethyl cellulose, acrylic resins such as EUDRAGIT® coatings(available from Rohm & Haas G.M.B.H. of Darmstadt, Germany), waxes,shellac, polyvinylpyrrolidone, and other commercially availablefilm-coating preparations such as Dri-Klear, manufactured by Crompton &Knowles Corp., Mahwah, N.J. or OPADRY® manufactured by Colorcon, Inc.,of West Point, Pa.

[0107] Compositions for oral administration can also have liquid forms.For example, suitable liquid forms include aqueous solutions, emulsions,suspensions, solutions reconstituted from non-effervescent granules,suspensions reconstituted from non-effervescent granules, effervescentpreparations reconstituted from effervescent granules, elixirs,tinctures, syrups, and the like. Liquid orally administered compositionstypically comprise (A) the active compound and (B) a carrier comprisingingredients selected from the group consisting of a) diluents, e)colorants, and f) flavors, g) sweeteners, j) preservatives, m) solvents,n) suspending agents, and o) surfactants. Peroral liquid compositionspreferably comprise one or more ingredients selected from the groupconsisting of e) colorants, f) flavors, and g) sweeteners.

[0108] Other compositions useful for attaining systemic delivery of theactive compounds include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as a) diluents including sucrose, sorbitol and mannitol; and c)binders such as acacia, microcrystalline cellulose,carboxymethylcellulose, and hydroxypropylmethylcellulose. Suchcompositions may further comprise b) lubricants, e) colorants, f)flavors, g) sweeteners, h) antioxidants, and k) glidants.

[0109] The composition may further comprise component (C) one or moreoptional ingredients. Component (C) can be a therapeutic agent used totreat the underlying disease from which the subject suffers. Forexample, component (C) can be (i) a cancer therapeutic agent, such as achemotherapeutic agent or a chemosensitizing agent, or a combinationthereof; (ii) an antibacterial agent, (iii) an antiviral agent, (iv) anantifungal agent, and combinations thereof. Component (C) can becoadministered with component (A) to increase the susceptibility of themultidrug resistant cells within the subject to the therapeutic agent.

[0110] Suitable (i) cancer therapeutic agents are known in the art.Cancer therapeutic agents include chemotherapeutic agents,chemosensitizing agents, and combinations thereof. Suitablechemotherapeutic agents are disclosed in U.S. Pat. No. 5,416,091, whichis hereby incorporated by reference for the purpose of disclosingchemotherapeutic agents. Suitable chemotherapeutic agents includeactinomycin D, adriyamycin, amsacrine, colchicine, daunorubicin,docetaxel (which is commercially available as TAXOTERE® from AventisPharmaceuticals Products, Inc.), doxorubicin, etoposide, mitoxantrone,mytomycin C, paclitaxel (which is commercially available as TAXOL® fromBristol-Myers Squibb Company of New York, N.Y.), tenipaside,vinblastine, vincristine, and combinations thereof.

[0111] Suitable chemosensitizing agents include calcium channelblockers, calmodulin antagonists, cyclic peptides, cyclosporins andtheir analogs, phenothiazines, quinidine, reserpine, steroids,thioxantheres, transflupentixol, trifluoperazine, and combinationsthereof. Suitable chemosensitizing agents are disclosed by Amudkar, et.al in “Biochemical, Cellular, and Pharmacological Aspects of theMultidrug Transporter,” Annu. Rev. Pharmacol. Toxicol., 39, pp. 361-398(1999).

[0112] Suitable (ii) antibacterial agents, (iii) antiviral agents, and(iv) antifungal agents are known in the art (see “Annual Reports onMedicinal Chemistry—33; Section III Cancer and Infectious Diseases” ed.Plattner, J., Academic Press, Ch. 12, pp. 121-130 (1998)). Suitableantibacterial agents include quinolones, fluoroquinolones, ®-lactamantibiotics, aminoglycosides, macrolides, glycopeptides, tetracyclines,and combinations thereof.

[0113] Suitable (iii) antiviral agents include protease inhibitors, DNAsynthase inhibitors, reverse transcription inhibitors, and combinationsthereof.

[0114] Suitable (iv) antifungal agents include azoles, such asketoconazole, fluconazole, itraconazole, and combinations thereof.

[0115] One skilled in the art will recognize that these therapeuticagents are exemplary and not limiting, and that some may be used in thetreatment of various multidrug resistant conditions and diseases. Oneskilled in the art would be able to select therapeutic agents withoutundue experimentation.

[0116] The amount of component (C) used in combination with component(A), whether included in the same composition or separatelycoadministered, will be less than or equal to that used in amonotherapy. Preferably, the amount of component (C) is less than 80% ofthe dosage used in a monotherapy. Monotherapeutic dosages of such agentsare known in the art.

[0117] Component (C) may be part of a single pharmaceutical compositionor may be separately administered at a time before, during, or afteradministration of component (A), or combinations thereof.

[0118] In a preferred embodiment, the composition of this inventioncomprises component (A), component (B), and (C) a chemotherapeuticagent. In an alternative preferred embodiment, the composition comprisescomponent (A), component (B), and (C) a chemosensitizing agent. Inanother preferred alternative embodiment, the composition comprisescomponent (A), component (B), and (C) both a chemotherapeutic agent anda chemosensitizing agent.

[0119] The exact amounts of each component in the systemic compositionsdepend on various factors. These factors include the specific compoundselected as component (A), and the mode by which the composition will beadministered. The amount of component (A) in the systemic composition istypically about 1 to about 99%.

[0120] The systemic composition preferably further comprises 0 to 99%component (C), and a sufficient amount of component (B) such that theamounts of components (A), (B), and (C), combined equal 100%. The amountof (B) the carrier employed in conjunction with component (A) issufficient to provide a practical quantity of composition foradministration per unit dose of the compound. Techniques andcompositions for making dosage forms useful in the methods of thisinvention are described in the following references: ModemPharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); andAnsel, Introduction to Pharmaceutical Dosage Forms, 2^(nd) Ed., (1976).

Topical Compositions

[0121] Topical compositions comprise: component (A), described above,and component (B) a carrier. The carrier of the topical compositionpreferably aids penetration of component (A) into the skin. Topicalcompositions preferably further comprise (C) the optional ingredientdescribed above.

[0122] Component (B) the carrier may comprise a single ingredient or acombination of two or more ingredients. In the topical compositions,component (B) is a topical carrier. Preferred topical carriers compriseone or more ingredients selected from the group consisting of water,alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils,mineral oil, propylene glycol, polypropylene glycol-2 myristylpropionate, dimethyl isosorbide, combinations thereof, and the like.More preferred carriers include propylene glycol, dimethyl isosorbide,and water.

[0123] The topical carrier may comprise one or more ingredients selectedfrom the group consisting of q) emollients, r) propellants, s) solvents,t) humectants, u) thickeners, v) powders, and w) fragrances in additionto, or instead of, the preferred topical carrier ingredients listedabove. One skilled in the art would be able to optimize carrieringredients for the topical compositions without undue experimentation.

[0124] Ingredient q) is an emollient. The amount of ingredient q) in thetopical composition is typically about 5 to about 95%. Suitableemollients include stearyl alcohol, glyceryl monoricinoleate, glycerylmonostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetylalcohol, isopropyl isostearate, stearic acid, isobutyl palmitate,isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate,decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate,di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropylstearate, butyl stearate, polyethylene glycol, triethylene glycol,lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylatedlanolin alcohols, petrolatum, mineral oil, butyl myristate, isostearicacid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyllactate, decyl oleate, myristyl myristate, polydimethylsiloxane, andcombinations thereof. Preferred emollients include stearyl alcohol andpolydimethylsiloxane.

[0125] Ingredient r) is a propellant. The amount of ingredient r) in thetopical composition is typically about 5 to about 95%. Suitablepropellants include propane, butane, isobutane, dimethyl ether, carbondioxide, nitrous oxide, nitrogen, and combinations thereof.

[0126] Ingredient s) is a solvent. The amount of ingredient s) in thetopical composition is typically about 5 to about 95%. Suitable solventsinclude water, ethyl alcohol, methylene chloride, isopropanol, castoroil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether,diethylene glycol monoethyl ether, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, and combinations thereof. Preferred solventsinclude ethyl alcohol.

[0127] Ingredient t) is a humectant. The amount of ingredient t) in thetopical composition is typically about 5 to about 95%. Suitablehumectants include glycerin, sorbitol, sodium2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate,gelatin, and combinations thereof. Preferred humectants includeglycerin.

[0128] Ingredient u) is a thickener. The amount of ingredient u) in thetopical composition is typically 0 to about 95%.

[0129] Ingredient v) is a powder. The amount of ingredient v) in thetopical composition is typically 0 to about 95%. Suitable powdersinclude chalk, talc, fullers earth, kaolin, starch, gums, colloidalsilicon dioxide, sodium polyacrylate, tetraalkyl ammonium smectites,trialkyl aryl ammonium smectites, chemically modified magnesium aluminumsilicate, organically modified montmorillonite clay, hydrated aluminumsilicate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, ethylene glycol monostearate, and combinations thereof.

[0130] Ingredient w) is a fragrance. The amount of ingredient w) in thetopical composition is typically about 0.001 to about 0.5%, preferablyabout 0.001 to about 0.1%.

[0131] Ingredient x) is a wax. Waxes useful in this invention areselected from the group consisting of animal waxes, vegetable waxes,mineral waxes, various fractions of natural waxes, synthetic waxes,petroleum waxes, ethylenic polymers, hydrocarbon types such asFischer-Tropsch waxes, silicone waxes, and mixtures thereof wherein thewaxes have a melting point between 40 and 100° C. The amount ofingredient x) in the topical composition is typically about 1 to about99%.

[0132] In an alternative embodiment of the invention, the activecompounds may also be administered in the form of liposome deliverysystems, such as small unilamellar vesicles, large unilamellar vesicles,and multilamellar vesicles. Liposomes can be formed from a variety ofphospholipids, such as cholesterol, stearylamine orphosphatidylcholines. A preferred composition for topical delivery ofthe present compounds uses liposomes as described in Dowton et al.,“Influence of Liposomal Composition on Topical Delivery of EncapsulatedCyclosporin A: I. An in vitro Study Using Hairless Mouse Skin”, S.T.P.Pharma Sciences, Vol. 3, pp. 404-407 (1993); Wallach and Philippot, “NewType of Lipid Vesicle: Novasome®”, Liposome Technology, Vol. 1, pp.141-156 (1993); U.S. Pat. No. 4,911,928, and 5,834,014.

[0133] The exact amounts of each component in the topical compositiondepend on various factors. Including the specific compound selected forcomponent (A) and the mode by which the composition will beadministered. However, the amount of component (A) typically added tothe topical composition is about 0.1 to about 99%, preferably about 1 toabout 10%.

[0134] The topical composition preferably further comprises 0 to about99% component (C), more preferably 0 to abut 10%, and a sufficientamount of component (B) such that the amounts of components (A), (B),and (C), combined equal 100%. The amount of (B) the carrier employed inconjunction with component (A) is sufficient to provide a practicalquantity of composition for administration per unit dose of thecompound. Techniques and compositions for making dosage forms useful inthe methods of this invention are described in the following references:Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); andAnsel, Introduction to Pharmaceutical Dosage Forms, 2^(nd) Ed., (1976).

[0135] Topical compositions that can be applied locally to the skin maybe in any form including solutions, oils, creams, ointments, gels,lotions, shampoos, leave-on and rinse-out hair conditioners, milks,cleansers, moisturizers, sprays, skin patches, and the like.

[0136] Component (A) may be included in kits comprising component (A), asystemic or topical composition described above, or both; andinformation, instructions, or both that use of the kit will providetreatment for multidrug resistance (particularly in humans). Theinformation and instructions may be in the form of words, pictures, orboth, and the like. In addition or in the alternative, the kit maycomprise component (A), a composition, or both; and information,instructions, or both, regarding methods of administration of component(A) or the composition, preferably with the benefit of treatingmultidrug resistance in mammals.

[0137] In an alternative embodiment of the invention, components (A) and(C) may be included in kits comprising components (A) and (C), systemicor topical compositions described above, or both; and information,instructions, or both that use of the kit will provide treatment formultidrug resistance (particularly humans). The information andinstructions may be in the form of words, pictures, or both, and thelike. In addition or in the alternative, the kit may comprise components(A) and (C), compositions, or both; and information, instructions, orboth, regarding methods of administration of components (A) and (C) orthe compositions, preferably with the benefit of treating multidrugresistance in mammals.

Methods of Use of the Invention

[0138] This invention relates to a method of inhibiting a transportprotein. The method comprises administering to a mammal in need oftreatment, (A) an active compound described above.

[0139] This invention further relates to a method for treating multidrugresistance. The method comprises administering to a mammal (preferably ahuman) suffering from multidrug resistance, (A) an active compounddescribed above. For example, a mammal diagnosed with multidrugresistant cancer can be treated by the methods of this invention.Preferably, a systemic or topical composition comprising (A) the activecompound and (B) the carrier is administered to the mammal. Morepreferably, the composition is a systemic composition comprising (A) theactive compound, (B) the carrier, and (C) an optional ingredient such asa therapeutic agent. Component (A) may be administered before, during,or after administration of component (C). A preferred administrationschedule is a continuous infusion over the 24 hour period during whichcomponent (C) is also administered.

[0140] The dosage of component (A) administered depends on variousfactors, including the method of administration, the physical attributesof the subject (e.g., age, weight, and gender), and the condition fromwhich the subject suffers. Effective dosage levels for treating orpreventing MDR range from about 0.01 to about 100 mg/kg body weight perday, preferably about 0.5 to about 50 mg/kg body weight per day of (A) acompound of this invention. These dosage ranges are merely exemplary,and daily administration can be adjusted depending on various factors.The specific dosage of the active compound to be administered, as wellas the duration of treatment, and whether the treatment is topical orsystemic are interdependent. The dosage and treatment regimen will alsodepend upon such factors as the specific active compound used, thetreatment indication, the efficacy of the active compound, the personalattributes of the subject (such as, for example, weight, age, sex, andmedical condition of the subject), compliance with the treatmentregimen, and the presence and severity of any side effects of thetreatment.

[0141] In addition to the benefits in treating multidrug resistance insubjects suffering from cancer, the active compounds in the compositionsand methods of this invention can also be used to treat otherconditions. These other conditions include other types of multidrugresistance (i.e., in addition to cancer multidrug resistance) such asbacterial, viral, and fungal multidrug resistance. For example, many ofthe FDA approved HIV protease inhibitors used to treat AIDS patientssuffering from the HIV virus are substrates for Pgp. Therefore, in analternative embodiment of this invention, an active compound of thisinvention is coadministered with a therapeutic agent such as an HIVprotease inhibitor.

[0142] The active compounds and compositions of this invention can alsobe administered with other therapeutic agents such as oral drugs. Theactive compounds and compositions can be used to enhance oral drugabsorption and increase bioavailability of various drugs.

[0143] The active compounds and compositions can also be used to aiddrug delivery through the blood-brain barrier for, e.g., enhancing theeffectiveness of drugs to treat Alzheimer's disease, treating memorydisorders, enhancing memory performance, or treating any other centralnervous system disorder where drug delivery is compromised via thistransport pump mechanism.

[0144] The active compounds and compositions can also be administered totreat subjects suffering from neurological disorders such as spinalinjuries, diabetic neuropathy, and macular degeneration.

[0145] The active compounds and compositions can also be administered totreat subjects suffering from vision disorders and to improve vision.

[0146] The active compounds and compositions can also be administered totreat hair loss. “Treating hair loss” includes arresting hair loss,reversing hair loss, and promoting hair growth.

[0147] The active compounds and compositions can also be adminstered totreat inflammatory diseases. Inflammatory diseases include irritablebowel disease, arthritis, and asthma.

EXAMPLES

[0148] These examples are intended to illustrate the invention to thoseskilled in the art and should not be interpreted as limiting the scopeof the invention set forth in the claims. The active compounds of thisinvention can be made using conventional organic syntheses, which arereadily available to one skilled in the art without undueexperimentation. Such syntheses can be found in standard texts such asJ. March, Advanced Organic Chemistry, John Wiley & Sons, 1992. One ofordinary skill in the art will appreciate that certain reactions arebest carried out when other functionalities are masked or protected inthe compound, thus increasing the yield of the reaction or avoiding anyundesirable side reactions. The skilled artisan may use protectinggroups to accomplish the increased yields or to avoid the undesiredreactions. These reactions can be found in the literature, see forexample, Greene, T. W. and Wuts, P. G. M., Protecting Groups in OrganicSynthesis, 2^(nd) ed., John Wiley & Sons, 1991.

[0149] The starting materials for preparing the compounds of theinvention are known, made by known methods, or commercially available.The starting materials for preparing the compounds of the invention mayinclude the following.

[0150] The following reagents are available from Aldrich ChemicalCompany, Milwaukee, Wis.: 1-bromo-3-phenylpropane, 5-hydroxyquinoline,(R)-(−)-glycidyl tosylate, 3,4-pyridinedicarboxylic acid,4-phenylbutylamine, 3-pyridinepropionic acid, tert-butyl[S-(R*,R*)]-(−)-(1-oxiranyl)-2-phenylethyl)carbamate, epichlorohydrin,3,4,5-trimethoxybenzoyl chloride, N,N-diisopropylethylamine,4-dimethylaminopyridine, 1-hydroxybenzotriazole,4-trans-aminomethylcyclohexanecarboxylic acid,3,4,5-trimethoxybenzylamine, and 2,2,4-trimethyl-2-oxazoline. Thefollowing reagents are available from Lancaster Synthesis Inc., Windham,NH: 4-phenylbutyronitrile, 1-tert-butoxycarbonyl-piperidine-3-carboxylicacid, 1-benzyl-4-aminopiperidine, 3,4-dimethoxybenzenesulfonyl chloride,and 1-benzyl-4-homopiperazine.

[0151] The following reagents are available from Fluka Chemie AG,Milwaukee, Wis.: 1-tert-butoxycarbonyl-piperidine-4-carboxylic, and(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(“PyBOP”), N-(tert-butoxycarbonyl)-iminodiacetic acid, and1-(diphenylmethyl)piperazine.

[0152] The following reagents are available from Acros Organics,Pittsburgh, Pa.: quinoline-6-carboxylic acid and quinoline-5-carboxylicacid.

[0153] The following reagent is available from Bachem Bioscience, Kingof Prussia, Pa.: tert-butoxycarbonyl-β-(3-pyridyl)-alanine.

[0154] The following reagents are available from Sigma Chemical Company,Milwaukee, Wis.: N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride and N-tert-butoxycarbonyl)-(N-methyl)-2-aminoacetic acid.

[0155] Various abbreviations are used herein. Abbreviations that can beused and their definitions are shown below in Table 2. TABLE 2Abbreviations Abbreviation Definition “AM” acetoxymethyl ester “Boc”tert-butoxycarbonyl “CIMS” chemical ionization mass spectrometry “DMF”dimethylformamide “ESMS” electrospray mass spectrometry “Et” an ethylgroup “Me” a methyl group “MH+” parent ion in ESMS “MS” massspectrometry “MTT”3-[4,5-dimethyl-thiazoyl-2-yl]2,5-diphenyl-tetrazolium bromide “NIH”National Institute of Health “PBS” Phosphate-buffered saline “THF”tetrahydrofuran

Reference Example 1 Method for Measuring Activity to Inhibit Pgp(Reversal Assay)

[0156] NIH-MDR1-G185 cells (obtained from M. Gottesman, NIH) wereharvested and resuspended at 6×10⁴ cells/ml in RPMI 1640 containingL-glutamine, 10% Cosmic calf serum, and penicillin-streptomycin. Cellsuspension aliquots of 100 microliters were added to individual wells ofa 96 well microtiter plate and incubated overnight at 37° C. to allowcells to adhere. Cell viability in the presence of an anticancer drugwas determined in the presence and absence of an MDR modifying agentusing an MTT assay (P. A. Nelson, et. al, J. Immunol, 150:2139-2147(1993)).

[0157] Briefly, cells were preincubated with an MDR modulating agent(final concentration 5 micromolar) for 15 min at 37° C., then treatedwith varying concentrations of an anticancer agent for 72 hr at 37° C.MTT dye (20 microliters of 5 mg/ml PBS solution) was added to each welland incubated for 4 hr at 37° C. Media was carefully removed and dye wassolubilized with 100 microliters of acidified isopropyl alcohol.Absorption was measured on a spectrophotometric plate reader at 570 nmand corrected for background by subtraction at 630 nm. Reversal indexwas calculated for each MDR modulator and normalized to the reversalindex of a benchmark modulator, VX-710 as below:

[0158] Reversal index=IC₅₀ in the absence of modulator/IC₅₀ in thepresence of modulator Normalized reversal index=Reversal index ofmodulator Reversal index of VX-710

[0159] VX-710 is(S)-N-[2-Oxo-2-(3,4,5-trimethoxyphenyl)acetyl]piperidine-2-carboxylicacid 1,7-bis(3-pyridyl)-4-heptyl ester.

Reference Example 2 Method for Measuring Activity to Inhibit Pgp andMRP1 (Calcein AM Extrusion Assay)

[0160] Pgp-dependent calcein AM extrusion was measured in NIH-MDR1-G185cells or HL60-MDR1 cells. MRP1-dependent calcein AM extrusion wasmeasured in HL60/ADR cells. Dye uptake was measured by incubating0.5-1×10⁶ cells/ml in cell culture medium containing 0.25 mM calcein AMat 37° C. at an excitation wavelength=493 nm and an emissionwavelength=515 nm. Inhibition of calcein AM transport by varyingconcentrations of MDR modulators was determined by measuring the rate ofincrease in fluorescence of free calcein for 5 min periods. The IC₅₀values were obtained by determining the concentration of modulatorresulting in 50% of the maximum transport inhibition. Maximum transportinhibition was the % inhibition produced in the presence of 50-60microliters verapmil.

Reference Example 3 Fluorescent Substrate Accumulation Assay

[0161] NIH-MDR1-G185 cells (obtained from M. Gottesman, NIH) wereharvested and resuspended in RPMI-1640 containing L-glutamine, 10%Cosmic Calf Serum and penicillin-streptomycin. Cell suspension aliquotsof 175 microliters (1×10⁵ cells) were added to individual wells of a 96well microtiter plate and preincubated for 15 min at 37° C. with 20microliters MDR modulator diluted in cell culture media to give a finalconcentration of 10 micromolar. Control wells received no modulatingagent. BODIPY-FL Taxol (Molecular Probes, Eugene, Oreg.) was added toeach well in 10 microliter aliquots to give a final concentration of 500nM and cells were incubated for 40 min at 37° C. Cells were centrifugedat 100×g for 5 min at 4° C. and the cell pellet washed with 200microliters cold PBS to remove fluorescent medium from wells. Cells werecentrifuged once more, media removed, and cells resuspended in 200microliters cold PBS. Fluorescence accumulation was measured in afluorescence plate reader fitted with an excitation filter of 485 nm andan emission filter of 538 nm. BODIPY-FL taxol accumulation in the cellswas calculated as follows: Accumulation Index=(fluorescence inNIH-MDR1-G185 cells in the presence of modulator)/(fluorescence inNIH-MDR1-G185 cells in absence of modulator)

Reference Example 4 Method for Measuring Substrate Potential for MDR1(MDR1 ATPase assay)

[0162] Recombinant baculovirus carrying the human MDR1 gene wasgenerated and Sf9 cells infected with virus. The virus-infected cellswere harvested and their membranes isolated. MDR1-ATPase activity of theisolated Sf9 cell membranes was estimated by measuring inorganicphosphate liberation as previously described (B. Sarkadi, J. Biol.Chem., 1992, 267:4854-4858). The differences between the ATPaseactivities measured in the absence and presence of 100 micromolarvanadate were determined as activity specific to MDR1. MDR modulatorconcentrations causing half-maximum activation (Ka) or half-maximuminhibition of the MDR1-ATPase stimulated by 30-40 micromolar verapamil(Ki) were determined.

Example 1 Preparation of 1,7-diphenyl-4-aminoheptane hydrochloride (1)

[0163]

[0164] Magnesium (40.2 g, 1.65 mol) and anhydrous ether (3.2 L) arecombined in a reaction vessel with stirring. A solution of1-bromo-3-phenyl propane in 1.6 L of anhydrous ether is added to anaddition funnel. The bromide solution is added dropwise to the stirringreaction vessel over a 1 hour period. Upon completion of addition, themixture stirs for 1-2 hours. A solution of 4-phenylbutyronitrile (160 g,1.1 mol) in anhydrous ether (2.4 L) is placed in the addition funnel.The solution is added to the reaction vessel over a 1 hour time period.Upon complete addition the solution is heated to reflux for 10 hours,and then stirs at room temperature for six hours. The reaction mixtureis diluted with methanol (3.2 L) using an addition funnel. Sodiumborohydride (83.4 g, 2.2 mol) is added in portions. Upon completeaddition the reaction is stirred at room temperature for six hours. Thereaction mixture is quenched by a slow addition of water (3.2 L). Themixture is diluted with ether (3.2 L) and water (1.6 L). The ether layeris separated and the aqueous layer is extracted twice with ether (3.2L×2). The combined ether extracts are washed once with sodium chloridesolution, dried, filtered, and concentrated in vacuo to give the crudeproduct. This product is diluted in ether (1.2 L) and acidified by slowaddition of 1M HCl (1.2 L). The mixture stirs for one hour and isconcentrated in vacuo. The resulting precipitate is diluted withacetonitrile and is stirred for 16 hours. The desired1,7-diphenyl-4-aminoheptane hydrochloride is collected by filtration.

Example 2 Preparation of (R)-5-oxiranylmethoxy-guinoline (2)

[0165]

[0166] Sodium hydride (60 weight %; 1.79 g; 44.8 mmol) is washed withhexanes (3×10 mL) under an argon blanket. DMF (17 mL) is then added atambient temperature and the stirred slurry is cooled to 5° C. A solutionof 5-hydroxyquinoline (5.00 g; 34.4 mmol) in DMF (65 mL) is addeddropwise over 30 minutes. The resulting mixture is allowed to warm toambient temperature over 1 hour affording a clear, reddish-brownsolution. A solution of (R)-(−)-glycidyl tosylate (10.22 g; 44.8 mmol)in DMF (50 mL) is added dropwise over 20 minutes. The resulting mixtureis stirred at ambient temperature for 4 hours, quenched by the additionof saturated aqueous ammonium chloride (25 mL), poured onto water (750mL), and extracted with ether (3×375 mL). The combined ether layers arewashed with saturated aqueous sodium bicarbonate (2×375 mL), then driedover MgSO₄, filtered, and concentrated in vacuo. The residue is purifiedvia silica gel chromatography with gradient elution (33%→50% ethylacetate in hexanes) affording the desired product (4.95 g) as a tansolid. ESMS:MH⁺ 202.2 (base).

Example 3 Preparation of4-[4-phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-piperidine-1-carboxylicacid tert-butyl ester (3)

[0167]

[0168] 1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (1 g; 4.36mmol) is dissolved in methylene chloride (25 mL) at ambient temperature.1,7-Diphenyl-4-aminoheptane hydrochloride (1) (1.33 g; 4.38 mmol),triethylamine (1.22 mL; 8.75 mmol), andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.92 g;4.8 mmol) are added sequentially. The mixture is stirred for 18 hours atambient temperature then concentrated in vacuo at 40° C. The residue isdiluted with ethyl acetate (150 mL) and washed successively with water(150 mL), 0.1 N HCl (100 mL), saturated aqueous sodium bicarbonate (50mL), and saturated brine (50 mL). The organic layer is dried over MgSO₄,filtered, and concentrated in vacuo. The residue is purified via silicagel chromatography with gradient elution (5%→40% ethyl acetate inhexanes) affording the desired product (0.77 g) as a solid.

Example 4 Preparation of piperidine-4-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4)

[0169]

[0170]4-[4-Phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-piperidine-1-carboxylicacid tert-butyl ester (3) (0.77 g; 1.61 mmol) is dissolved in methylenechloride (20 mL) at ambient temperature. Trifluoroacetic acid (20 mL) isadded in a slow stream, and the solution is stirred for 90 minutes atambient temperature. The solution is concentrated in vacuo at 40° C. Theresidue is slurried in a mixture of methylene chloride (10 mL) and water(100 mL), then potassium carbonate is added until the slurry isalkaline. The slurry is diluted with water (200 mL) then extracted withmethylene chloride (3×100 mL). The organic extracts are dried overMgSO₄, filtered, and concentrated in vacuo affording the desired product(0.58 g) as an oil.

Example 5 Preparation of(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-4-carboxylicacid ]4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (5)

[0171]

[0172] Piperidine-4-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (150.7 mg; 0.4 mmol) isdissolved in isopropanol (10 mL) at ambient temperature.(R)-5-Oxiranylmethoxy-quinoline (2) (79.8 mg; 0.4 mmol) is added, thenthe mixture is heated to 70° C. and maintained for 18 hours. Aftercooling to ambient temperature, the solution is concentrated in vacuo at40° C. The residue is purified via silica gel chromatography withgradient elution (10%→100% acetone in hexanes) affording the desiredproduct (118.2 mg) as a white solid. ESMS:MH⁺ 580.4 (base).

Example 6 Preparation of1-[2-hydroxy-3-(3,4,5-trimethoxyphenyl)-propyl]-piperidine-4-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl]amide (6)

[0173]

[0174] Piperidine-4-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (150.7 mg; 0.4 mmol) isdissolved in isopropanol (10 nL) at ambient temperature.(+/−)-2-(3,4,5-Trimethoxy-phenoxymethyl)-oxirane (95.2 mg; 0.4 mmol) isadded, then the mixture is heated to 70° C. and maintained for 18 hours.After cooling to ambient temperature, the solution is concentrated invacuo at 40° C. The residue is purified via silica gel chromatographywith gradient elution (10%→100% acetone in hexanes) affording thedesired product (145.9 mg) as an oil. ESMS: MH⁺ 619.4 (base).

Example 7 Preparation of pyridine-3,4-dicarboxylic acidbis-[(4-phenyl-butyl)-amide] (7)

[0175]

[0176] 3,4-Pyridinedicarboxylic acid (1 g; 6.0 mmol) is slurried in DMF(50 mL) at ambient temperature. To this reaction mixture is addedsequentially 1-hydroxybenzotriazole hydrate (2.43 g; 18.0 mmol),4-phenylbutylamine (2.08 mL; 13.2 mmol), triethylamine (1.67 mL; 12.0mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(2.87 g; 15.0 mmol). The reaction mixture is stirred for 18 hours atambient temperature. The batch is poured onto ethyl acetate (300 mL),then extracted sequentially with water (100 mL), IN HCl (100 mL),saturated aqueous sodium bicarbonate (50 mL), and brine (50 mL). Theorganic phase is dried over MgSO₄, filtered, and concentrated in vacuoaffording the desired product (2.65 g) as a semi-solid. ESMS:MH⁺ 430.0.

Examples 8 and 9 Preparation of trans- piperidine-3,4-dicarboxylic acidbis[(4-phenyl-butyl)-amide] (8) and cis- piperidine-3,4-dicarboxylicacid bis[(4-phenyl-butyl)-amide] (9)

[0177]

[0178] Pyridine-3,4-dicarboxylic acid bis-[(4-phenyl-butyl)-amide] (7)(0.46 g; 1.07 mmol) is combined with ethanol (20 mL) and 20% Pd(OH)₂ oncarbon (0.4 g) in a hydrogenation bottle. The mixture is hydrogenated at50 psi for 18 hours, then additional 20% Pd(OH)₂ on carbon (0.25 g) isadded to the mixture and the hydrogenation is resumed for an additional18 hours. The mixture is filtered through a celite pad and washed withethanol. The combined filtrate plus wash is concentrated in vacuo. Theresidue is purified via silica gel chromatography with gradient elution(5%→100% methanol in methylene chloride) affording the desired productsas separable diastereomers.

[0179] The first eluted diastereomer is (8) 70.9 mg; ESMS:MH⁺ 436.4(base). The second eluted diastereomer is (9) 78.1 mg; ESMS:MH⁺ 436.4(base).

Example 10 Preparation oftrans-(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-3,4-dicarboxylicacid bis-[(4-phenyl-butyl)-amide] (10)

[0180]

[0181] trans- Piperidine-3,4-dicarboxylic acidbis[(4-phenyl-butyl)-amide] (8) (78.1 mg; 0.179 mmol) is dissolved inisopropanol (10 mL) at ambient temperature.(R)-5-Oxiranylmethoxy-quinoline (2) (36.1 mg; 0.179 mmol) is added thenthe mixture is heated to 70° C. and maintained for 18 hours. Aftercooling to ambient temperature the solution is concentrated in vacuo at40° C. The residue is purified via silica gel chromatography withgradient elution (0%→50% methanol in methylene chloride) affording thedesired product (69.6 mg) as a solid. ESMS:MH⁺ 637.4 (base).

Example 11 Preparation of cis-(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-3,4-dicarboxylicacid bis-[(4-phenyl-butyl)-amide] (11)

[0182]

[0183] cis-Piperidine-3,4-dicarboxylic acid bis[(4-phenyl-butyl)-amide](9) (70.9 mg; 0.163 mmol) is dissolved in isopropanol (10 mL) at ambienttemperature. (R)-5-Oxiranylmethoxy-quinoline (2) (32.8 mg; 0.163 mmol)is added then the mixture is heated to 70° C. and maintained for 18hours. After cooling to ambient temperature the solution is concentratedin vacuo at 40° C. The residue is purified via silica gel chromatographywith gradient elution (0%→50% methanol in methylene chloride) affordingthe desired product (86.0 mg) as an oil. ESMS:MH⁺ 637.4 (base).

Example 12 Preparation of3-[4-phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-piperidine-1-carboxylicacid tert-butyl ester (12)

[0184]

[0185] 1-tert-Butoxycarbonyl-piperidine-3-carboxylic acid (1 g; 4.36mmol) is dissolved in methylene chloride (50 mL) at ambient temperature.1,7-Diphenyl-4-aminoheptane hydrochloride (1) [1.33 g; 4.36 mmol],triethylamine (0.61 mL; 4.36 mmol), andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.84 g;4.4 mmol) are added sequentially. The mixture is stirred for 18 hours atambient temperature then concentrated in vacuo at 30° C. The residue isdiluted with ethyl acetate (100 mL) and washed successively with water(200 mL), saturated aqueous sodium bicarbonate (50 mL), and saturatedbrine (50 mL). The organic layer is dried over MgSO₄, filtered, andconcentrated in vacuo. The residue is purified via silica gelchromatography with gradient elution (5%→40% ethyl acetate in hexanes)affording the desired product (1.30 g) as a viscous oil. ESMS:MH⁺ 479.4

Example 13 Preparation of piperidine-3-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (13)

[0186]

[0187]3-[4-Phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-piperidine-1-carboxylicacid tert-butyl ester (12) (0.202 g; 0.42 mmol) is dissolved inmethylene chloride (5 mL) at ambient temperature. Trifluoroacetic acid(5 mL) is added in a slow stream, and the solution is stirred for 90minutes at ambient temperature. The solution is concentrated in vacuo at40° C. The residue is slurried in a mixture of methylene chloride (10mL) and water (100 mL), then potassium carbonate is added until theslurry is alkaline. The slurry is diluted with water (50 mL) thenextracted with methylene chloride (3×50 mL). The organic extracts aredried over MgSO₄, filtered, and concentrated in vacuo affording thedesired product (0.147 g) as an oil.

Example 14 Preparation of(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-3-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl-amide (14)

[0188]

[0189] Piperidine-3-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (13) (146.6 mg; 0.39 mmol) isdissolved in isopropanol (10 mL) at ambient temperature.(R)-5-Oxiranylmethoxy-quinoline (2) (80.0 mg; 0.39 mmol) is added, thenthe mixture is heated to 70° C. and maintained for 18 hours. Aftercooling to ambient temperature, the solution is concentrated in vacuo at40° C. The residue is purified via silica gel chromatography withgradient elution (10%→100% acetone in hexanes) affording the desiredproduct as a solid. ESMS:MH⁺ 580.4 (base).

Example 15 Preparation of(R)-1-[2-hydroxy-3-(3,4,5-trimethoxyphenyl)-propyl]piperidine-3-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl-amide (15)

[0190]

[0191] Piperidine-3-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (13) (150 mg; 0.4 mmol) isdissolved in isopropanol (10 mL) at ambient temperature.(R)-2-(3,4,5-Trimethoxy-phenoxymethyl)-oxirane (95.2 mg; 0.4 mmol) isadded, then the mixture is heated to 70° C. and maintained for 18 hours.After cooling to ambient temperature, the solution is concentrated invacuo at 40° C. The residue is purified via silica gel chromatographywith gradient elution (1%→-20% methanol in methylene chloride) affordingthe desired product (220.3 mg) as an oil. ESMS: MH⁺ 619.4 (base).

Example 16 Preparation of1-(3-pyridin-3-yl-propionyl)-piperidine-3-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (16)

[0192]

[0193] Piperidine-3-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (13) (150 mg; 0.4 mmol) isdissolved in methylene chloride (10 mL) at ambient temperature.3-Pyridinepropionic acid (60.0 mg; 0.4 mmol), triethylamine (0.111 mL;0.4 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (0.0836 g; 0.4 mmol) are added sequentially. The mixtureis stirred for 18 hours at ambient temperature then diluted withmethylene chloride (90 mL) and washed successively with water (40 mL),saturated aqueous sodium bicarbonate (40 mL), and saturated brine (25mL). The organic layer is dried over MgSO₄, filtered, and concentratedin vacuo. The residue is purified via silica gel chromatography withgradient elution (1%→20% methanol in methylene chloride) affording thedesired product (138.4 mg) as an oil. ESMS: MH⁺ 512.4 (base).

Example 17 Preparation of quinoline-6-carboxylic acid oxiranylmethylester (17)

[0194]

[0195] Quinoline-6-carboxylic acid (1 g; 5.78 mmol) is dissolved in DMF(10 mL) at ambient temperature. Epichlorohydrin (0.4517 mL; 5.59 mmol)is added followed by mortar ground potassium carbonate (0.80 g; 5.79mmol). The mixture is stirred at ambient temperature for 48 hours.Potassium iodide (96 mg; 0.58 mmol) is added and stirring is continuedat ambient temperature for 24 hours. The mixture is heated to 60° C. andmaintained for 72 hours. After cooling, the mixture is poured onto water(700 mL) and extracted with ethyl acetate (3×100 mL). The combinedorganic extracts are washed successively with water (100 mL), and brine(50 mL), then dried over MgSO₄, filtered, and concentrated in vacuo at30 C. The residue is purified via silica gel chromatography withgradient elution (20%→67% ethyl acetate in hexanes) affording thedesired product (270 mg) as a white solid. ESMS:MH⁺ 230.0 (base).

Example 18 Preparation of quinoline-6-carboxylic acid2-hydroxy-3-{3-[4-phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-piperidin-1-yl}-propylester (18)

[0196]

[0197] Piperidine-3-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (13) (150 mg; 0.4 mmol) isdissolved in isopropanol (10 mL) at ambient temperature.Quinoline-6-carboxylic acid oxiranylmethyl ester (17) (90.8 mg; 0.4mmol) is added, then the mixture is heated to 70° C. and maintained for18 hours. After cooling to ambient temperature, the solution isconcentrated in vacuo at 40° C. The residue is purified via silica gelchromatography with gradient elution (1%→20% methanol in methylenechloride) affording the desired product (203.4 mg) as an oil. ESMS: MH⁺608.4 (base).

Example 19 Preparation of(1-benzyl-2-hydroxy-3-{3-[4-phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-piperidine-1-yl}-propyl)-carbamicacid tert-butyl ester (19)

[0198]

[0199] Piperidine-3-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (13) (150 mg; 0.4 mmol) isdissolved in isopropanol (10 mL) at ambient temperature.tert-Butyl[S-(R*, R*)]-(−)-(1-oxiranyl)-2-phenylethyl)carbamate (104.4mg; 0.4 mmol) is added, then the mixture is heated to 70° C. andmaintained for 18 hours. After cooling to ambient temperature, thesolution is concentrated in vacuo at 40° C. The residue is purified viasilica gel chromatography with gradient elution (1%→20% methanol inmethylene chloride) affording the desired product (166.7 mg) as an oil.ESMS: MH⁺ 642.6 (base).

Example 20 Preparation of1-(3-amino-2-hydroxy-4-phenyl-butyl)-piperidine-3-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (20)

[0200]

[0201](1-Benzyl-2-hydroxy-3-{3-[4-phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-piperidine-1-yl}-propyl)-carbamicacid tert-butyl ester (19) (194.4 mg; 0.3 mmol) is dissolved inmethylene chloride (5 mL) at ambient temperature. Trifluoroacetic acid(5 mL) is added in a slow stream, and the solution is stirred for 90minutes at ambient temperature. The solution is concentrated in vacuo at40° C. The residue is slurried in a mixture of methylene chloride (10mL) and water (100 mL), then potassium carbonate is added until theslurry is alkaline. The slurry is diluted with water (50 mL) thenextracted with methylene chloride (3×50 mL). The organic extracts aredried over MgSO₄, filtered, and concentrated in vacuo affording thedesired product (150 mg) as an oil.

Example 21 Preparation of quinoline-6-carboxylic acid(1-benzyl-2-hydroxy-3-{3-[-phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-piperidin-1-yl}-propyl)-amide(21)

[0202]

[0203] 1-(3-Amino-2-hydroxy-4-phenyl-butyl)-piperidine-3-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (20) (150 mg; 0.28 mmol) isdissolved in methylene chloride (10 mL) at ambient temperature.6-Quinolinecarboxylic acid (48 mg; 0.28 mmol), triethylamine (0.0772 mL;0.55 mmol), and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (58.4 mg; 0.31 mmol) are added sequentially. The mixtureis stirred for 18 hours at ambient temperature then concentrated invacuo at 30° C. The residue is diluted with ethyl acetate (100 mL) andwashed successively with water (50 mL), saturated aqueous sodiumbicarbonate (50 mL), and saturated brine (50 mL). The organic layer isdried over MgSO₄, filtered, and concentrated in vacuo. The residue ispurified via silica gel chromatography with gradient elution (2%→20%methanol in methylene chloride) affording the desired productdiastereomers (70 mg) as an oil. ESMS:MH⁺ 697.6 (base).

Example 22 Preparation of 5-phenyl-2-(3-phenyl-propyl)-pentanoic acid(22)

[0204]

[0205] 2,2,4-Trimethyl-2-oxazoline (5.64 mL; 44.2 mmol) is dissolved inTHF (40 mL) in a dry, argon purged flask at ambient temperature. Thesolution is cooled to −78° C., then n-butyllithium in hexanes (31.3 mLof 1.6 M solution; 50 mmol) is added dropwise via syringe, followed by asolution of 1-bromo-3-phenylpropane (7.42 mL; 48.8 mmol) in THF (20 mL)dropwise via syringe. The cooling bath is removed and the solution isallowed to slowly warm to ambient temperature. After approximately 30minutes, the reaction is cooled to −78° C., then n-butyllithium inhexanes (31.3 mL of 1.6 M solution; 50 mmol) is added dropwise viasyringe, followed by a solution of 1-bromo-3-phenylpropane (7.42 mL;48.8 mmol) in THF (20 mL) dropwise via syringe. The reaction mixture isstirred overnight with very slow warming to ambient temperature. Thesolution is poured onto water (200 mL) and 1N HCl is added to make themixture acidic. The mixture is extracted with ether (150 mL), then madealkaline with 50% aqueous sodium hydroxide solution. The alkalinemixture is extracted with ether (3×100 mL). The combined ether extractsare dried over MgSO₄, filtered, and concentrated in vacuo. The residueis purified via silica gel chromatography with gradient elution (0%→33%ethyl acetate in hexanes) affording the dialkylated oxazolineintermediate (13.55 g) as a colorless liquid. ESMS:MH⁺ 349.6 (base). Thedialkylated oxazoline intermediate (1 g; 2.86 mmol) is dissolved indioxane (10 mL) at ambient temperature. 3N HCl (20 mL) is added and thesolution is heated to gentle reflux for 18 hours. After cooling, thereaction mixture is poured onto water (20 mL) and extracted with ether(3×30 mL). The combined ether extracts are washed successively withwater (20 mL), and brine (20 mL), then dried over MgSO₄, filtered, andconcentrated in vacuo at 40° C. affording the desired product (0.76g) asa solid. ESMS:MH⁺ 297.2.

Example 23 Preparation of 5-phenyl-2-(3-phenyl-propyl)-pentanoic acid(1-benzyl-piperidin-4-yl)-amide (23)

[0206]

[0207] 1-Benzyl-4-aminopiperidine (0.5 g; 2.63 mmol) is dissolved in DMF(25 mL) at ambient temperature. 5-Phenyl-2-(3-phenyl-propyl)-pentanoicacid (22) (0.78 g; 2.62 mmol), triethylamine (0.46 mL; 3.28 mmol),1-hydroxybenzotriazole (0.444 g; 3.28 mmol), andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.554 g;2.89 mmol) are added sequentially. The mixture is stirred for 18 hoursat ambient temperature then poured onto ethyl acetate (250 mL) andextracted successively with water (50 mL), saturated aqueous sodiumbicarbonate (50 mL), and brine (50 mL), then dried over MgSO₄, filtered,and concentrated in vacuo. The residue is purified via silica gelchromatography with gradient elution (10%→67% ethyl acetate in hexanes)affording the desired product (1.07 g) as a white solid. ESMS:MH⁺ 469.4(base).

Example 24 Preparation of 5-phenyl-2-(3-phenyl-propyl)-pentanoic acidpiperidin-4-ylamide (24)

[0208]

[0209] 5-Phenyl-2-(3-phenyl-propyl)-pentanoic acid(1-benzyl-piperidin-4-yl)-amide (23) (0.5 g; 1.07 mmol) is combined withethanol (25 mL) and 20% Pd(OH)₂ on carbon (0.2 g) in a hydrogenationbottle. The mixture is hydrogenated at 50 psi for 18 hours then filteredthrough a celite pad and washed with ethanol. The combined filtrate pluswash is concentrated in vacuo affording the desired product (0.38 g) asan oil. ESMS:MH⁺ 379.4 (base).

Example 25 Preparation of 5-phenyl-2-(3-phenyl-propyl)-pentanoic acid{1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidin-4-yl}-amide (25)

[0210]

[0211] 5-Phenyl-2-(3-phenyl-propyl)-pentanoic acid piperidin-4-ylamide(24) (100 mg; 0.264 mmol) is dissolved in isopropanol (10 mL) at ambienttemperature. (R)-5-Oxiranylmethoxyquinoline (2) (53.2 mg; 0.264 mmol) isadded, then the mixture is heated to 70° C. and maintained for 18 hours.After cooling to ambient temperature, the solution is concentrated invacuo at 40° C. The residue is purified via silica gel chromatographywith gradient elution (0%→25% methanol in methylene chloride) affordingthe desired product (117 mg) as a solid. ESMS: MH⁺ 580.4 (base).

Example 26 Preparation of1-(3,4,5-trimethoxyglyoxyl)-piperidine-3-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (26)

[0212]

[0213] Piperidine-3-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (13) (0.46 g; 1.23 mmol) isdissolved in N,N-dimethylformamide (25 mL) at ambient temperature. 3′,4′, 5′-Trimethoxyphenylglyoxylic acid (0.29 g; 1.23 mmol),N,N-diisopropylethylamine (0.31 g; 2.43 mmol) and PyBOP (0.63 g; 17.0mmol) are added sequentially. The reaction is stirred for 18 hr. at roomtemperature, then poured onto ice-cold 0.1N HCl (150 mL) and extractedwith ethyl acetate (150 mL). The layers are separated and the organiclayer washed successively with brine (100 mL), saturated NaHCO₃ solution(150 mL) and brine (100 mL). The organic solution is dried over MgSO₄,filtered and concentrated under reduced pressure. Purification of theproduct by chromatography on silica gel (4:6 hexane:ethyl acetate)affords the desired amide (26). MS (NH₃Cl): 601 (MH⁺)

Example 27 Preparation of 1-(3-butenoyl)-piperidine-4-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (27)

[0214]

[0215] Piperidine-4-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (1.00 g; 2.64 mmol) isdissolved in methylene chloride (30 mL) at ambient temperature.3-Butenoic acid (0.27 g; 3.17 mmol), N,N-diisopropylethylamine (0.75 g;5.81 mmol) and PyBOP (1.65 g; 3.17 mmol) are added sequentially. Thereaction is stirred for 27 hr. at room temperature, then concentratedunder reduced pressure. The residue is purified via silica gelchromatography with gradient elution (70%→90% ethyl acetate in hexanes)affording the desired product (27) as a solid. CIMS (NH₃Cl): 447 (MH⁺)

Example 28 Preparation of 1-(oxiranylacetyl)-piperidine-4-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (28)

[0216]

[0217] 1-(3-Butenoyl)-piperidine-4-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (27) (1.00 g; 2.24 mmol) andm-chloroperbenzoic acid (Aldrich Chemical Company; 71% by assay; 0.65 g;2.91 mmol) are combined in 10 mL of methylene chloride and refluxed for24 hours. The solution is stirred at ambient temperature for 72 hours,diluted with methylene chloride (50 mL) and shaken with 10% aqueousNa₂SO₃ (50 mL). The methylene chloride layer is separated and washedsuccessively with saturated aqueous NaHCO₃ solution and brine. Theorganic layer is dried over MgSO₄, filtered and concentrated in vacuo.The residue is purified by chromatography on silica gel using a gradientelution (80%→90% ethyl acetate in hexanes, then 50%→60% acetone inhexanes) affording 28 as a solid. CIMS (NH₃Cl): 463 (MH⁺)

Example 29 Preparation of1-{3-hydroxy-4-[2-(1,2,3,4-tetrahydroisoquinoline)]-butyryl}-piperidine-4-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (29)

[0218]

[0219] 1-(Oxiranylacetyl)-piperidine-4-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (28) (100 mg; 0.216 mmol) and1,2,3,4-tetrahydroisoquinoline (28.8 mg; 0.216 mmol) are combined inabsolute ethanol (10 mL) and refluxed for 18 hours. After cooling toambient temperature, the solution is concentrated in vacuo at 40° C. Theresidue is chromatographed on silica gel with a gradient elution(80%→90% ethyl acetate in hexanes, then 50%→60% acetone in hexanes)affording the desired product (29) as a solid. CIMS (NH₃CI): 596 (NH⁺)

Example 30 Preparation of(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-4-carboxylicacid ethyl ester (31)

[0220]

[0221] Piperidine-4-carboxylic acid ethyl ester (30) (0.75 g; 4.77 mmol)and (R)-5-oxiranylmethoxy-quinoline (2) 0.96 g; 4.77 mmol) are combinedin 95 mL of absolute ethanol. The mixture is heated to reflux for 8hours. After cooling to ambient temperature, the solution isconcentrated in vacuo at 40° C. The residue is chromatographed on silicagel with a gradient elution (90% ethyl acetate in hexanes, then 50%→60%acetone in hexanes) affording the desired product (29) as an oil. CIMS(NH₃CI): 359 (MH⁺)

Example 31 Preparation of lithium(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-4-carboxylate(32)

[0222]

[0223](R)-1-[2-Hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-4-carboxylicacid ethyl ester (31) (1.15 g; 3.21 mmol) is dissolved in 21 mL of a40:40:20 mixture of tetrahydrofuran:water:methanol. Lithium hydroxide(81 mg; 3.37 mmol) is added and the mixture stirred at ambienttemperature. After 4.5 hours, the mixture is concentrated in vacuo at40° C. Further drying on the vacuum pump affords the desired product(32) as a white solid.

Example 32 Preparation of(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-4-carboxylicacid 4-[1-(diphenylmethyl)-piperazine] amide (34)

[0224]

[0225] Lithium(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-4-carboxylate(32) (100 mg; 0.297 mmol) is dissolved in methylene chloride (3 mL) atambient temperature. 1-(Diphenylmethyl)piperazine (33) (80 mg; 0.312mmol), N,N-diisopropylethylamine (0.85 mg; 0.654 mmol) and PyBOP (186mg; 0.357 mmol) are added sequentially. The reaction is stirred for 18hr. at room temperature, then concentrated under reduced pressure. Theresidue is purified via silica gel chromatography with gradient elution(90% ethyl acetate in hexanes, then 50%→100% acetone in hexanes)affording the desired product (34) as a solid. CIMS (NH3CI): 565 (MH⁺)

Example 33 Preparation of(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-4-carboxylicacid 4-[1-(o-tolyl)-piperazine] amide (36)

[0226]

[0227] Lithium(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-4-carboxylate(32) (100 mg; 0.297 mmol) is dissolved in methylene chloride (3 mL) atambient temperature. 1-(o-Tolyl)piperazine hydrochloride (35) (66 mg;0.312 mmol), N,N-diisopropylethylamine (123 mg; 0.952 mmol) and PyBOP(186 mg; 0.357 mmol) are added sequentially. The reaction is stirred for18 hr. at room temperature, then concentrated under reduced pressure.The residue is purified via silica gel chromatography with gradientelution (90% ethyl acetate in hexanes, then 50%→100% acetone in hexanes)affording the desired product (36) as an oil. CIMS (NH₃CI): 489 (MH⁺)

Example 34 Preparation of(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-4-carboxylicacid 1-[4-(phenyl)-butyl] amide (38)

[0228]

[0229] Lithium(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-4-carboxylate(32) (100 mg; 0.297 mmol) is dissolved in methylene chloride (3 mL) atambient temperature. 4-Phenylbutylamine (37) (47 mg; 0.312 mmol),N,N-diisopropylethylamine (85 mg; 0.654 mmol) and PyBOP (186 mg; 0.357mmol) are added sequentially. The reaction is stirred for 18 hr. at roomtemperature, then concentrated under reduced pressure. The residue ispurified via silica gel chromatography with gradient elution (90% ethylacetate in hexanes, then 50%→100% acetone in hexanes) affording thedesired product (38) as a solid. CIMS (NH₃CI): 462 (MH⁺)

Example 35 Preparation of(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-4-carboxylicacid benzyl amide (40)

[0230]

[0231] Lithium(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-4-carboxylate(32) (100 mg; 0.297 mmol) is dissolved in methylene chloride (3 mL) atambient temperature. Benzylamine (39) (33 mg; 0.312 mmol),N,N-diisopropylethylamine (85 mg; 0.654 mmol) and PyBOP (186 mg; 0.357mmol) are added sequentially. The reaction is stirred for 18 hr. at roomtemperature, then concentrated under reduced pressure. The residue ispurified via silica gel chromatography with gradient elution (90% ethylacetate in hexanes, then 50%→100% acetone in hexanes) affording thedesired product (40) as an oil. CIMS (NH₃CI): 420 (MH⁺)

Example 36 Preparation of(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-4-carboxylicacid dibenzyl amide (42)

[0232]

[0233] Lithium(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-4-carboxylate(32) (100 mg; 0.297 mmol) is dissolved in methylene chloride (3 mL) atambient temperature. Dibenzylamine (41) (62 mg; 0.312 mmol),N,N-diisopropylethylamine (85 mg; 0.654 mmol) and PyBOP (186 mg; 0.357mmol) are added sequentially. The reaction is stirred for 18 hr. at roomtemperature, then concentrated under reduced pressure. The residue ispurified via silica gel chromatography with gradient elution (90% ethylacetate in hexanes, then 50%→100% acetone in hexanes) affording thedesired product (42) as a solid. CIMS (NH₃CI): 510 (MH⁺)

Example 37 Preparation of(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-3-carboxylicacid ethyl ester (44)

[0234]

[0235] Piperidine-3-carboxylic acid ethyl ester (43) (1.0 g; 6.36 mmol)and (R)-5-oxiranylmethoxy-quinoline (2) (1.28 g; 6.36 mmol) are combinedin 10 mL of absolute ethanol. The mixture is heated at reflux for 16hours. After cooling to ambient temperature, the solution isconcentrated in vacuo at 40° C. The residue is chromatographed on silicagel (1:1 acetone:hexanes) affording the desired product (44) as an oil.ESMS: MH⁺ 359

Example 38 Preparation of lithium(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-3-carboxylate(45)

[0236]

[0237](R)-1-[2-Hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-3-carboxylicacid ethyl ester (44) (0.739 g; 2.06 mmol) is dissolved in 20 mL of a2:2:1 mixture of tetrahydrofuran:water:methanol. Lithium hydroxide (52mg; 2.17 mmol) is added and the mixture stirred at ambient temperature.After 16 hours, the mixture is concentrated in vacuo at 40° C. Furtherdrying on the vacuum pump affords the desired product (45) as a whitesolid.

Example 39 Preparation of(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-3-carboxylicacid 4-[1-(diphenylmethyl)-piperazine] amide (46)

[0238]

[0239] Lithium(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-3-carboxylate(45) (100 mg; 0.297 mmol) is dissolved in methylene chloride (2 mL) atambient temperature. 1-(Diphenylmethyl)piperazine (33) (80 mg; 0.312mmol), N,N-diisopropylethylamine (0.85 mg; 0.654 mmol) and PyBOP (186mg; 0.357 mmol) are added sequentially. The reaction is stirred for 18hr. at room temperature, then concentrated under reduced pressure. Theresidue is purified via silica gel chromatography (1:1 acetone:hexanes)affording the desired product (46) as a solid. ESMS:MH⁺ 565

Example 40 Preparation of(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-3-carboxylicacid 4-[1-(o-tolyl)-piperazine] amide (47)

[0240]

[0241] Lithium(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-3-carboxylate(45) (100 mg; 0.297 mmol) is dissolved in methylene chloride (2 mL) atambient temperature. 1-(o-Tolyl)piperazine hydrochloride (35) (66 mg;0.312 mmol), N,N-diisopropylethylamine (123 mg; 0.952 mmol) and PyBOP(186 mg; 0.357 mmol) are added sequentially. The reaction is stirred for18 hr. at room temperature, then concentrated under reduced pressure.The residue is purified via silica gel chromatography (1:1acetone:hexanes) affording the desired product (47) as an oil. ESMS:MH⁺489

Example 41 Preparation of(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-3-carboxylicacid 1-[4-(phenyl)-butyl] amide (48)

[0242]

[0243] Lithium(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-3-carboxylate(45) (100 mg; 0.297 mmol) is dissolved in methylene chloride (2 mL) atambient temperature. 4-Phenylbutylamine (37) (47 mg; 0.312 mmol),N,N-diisopropylethylamine (85 mg; 0.654 mmol) and PyBOP (186 mg; 0.357mmol) are added sequentially. The reaction is stirred for 18 hr. at roomtemperature, then concentrated under reduced pressure. The residue ispurified via silica gel chromatography (1:1 acetone:hexanes) affordingthe desired product (48) as an oil. ESMS:MH⁺ 462

Example 42 Preparation of(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-3-carboxylicacid 1-[3,3-(diphenyl)-propyl] amide (50)

[0244]

[0245] Lithium(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-3-carboxylate(45) (100 mg; 0.297 mmol) is dissolved in methylene chloride (2 mL) atambient temperature. 3,3-Diphenylpropylamine (49) (66 mg; 0.312 mmol),N,N-diisopropylethylamine (85 mg; 0.654 mmol) and PyBOP (186 mg; 0.357mmol) are added sequentially. The reaction is stirred for 18 hr. at roomtemperature, then concentrated under reduced pressure. The residue ispurified via silica gel chromatography (1:1 acetone:hexanes) affordingthe desired product (50) as a solid. ESMS:MH⁺ 524

Example 43 Preparation of 1-tert-butoxycarbonyl-4-aminomethylpiperidine(51)

[0246]

[0247] 4-Aminomethylpiperidine (2.28 g; 20 mmol) is dissolved in drytoluene (25 mL) at ambient temperature. Benzaldehyde (2.03 mL; 20 mmol)is added in one portion and the solution is heated to azeotropic refluxfor 135 minutes (with concommitant removal of water from the reactionmedium). The reaction mixture is cooled to ambient temperature thendi-tert-butyl dicarbonate (4.8 g; 22 mmol) is added portionwise and theresulting solution is stirred at ambient temperature for 64 hours. Thesolution is concentrated to dryness in vacuo at 40° C., then 1N KHSO₄(22 mL) is added to the residue and the resulting mixture is stirredrapidly at ambient temperature for 4 hours. The mixture is extractedwith ether (3×20 mL), then the aqueous layer is basicified with 1N NaOH(30 mL). Solid NaCl is added to the alkaline aqueous layer, then it isextracted with dichloromethane (3×30 mL). The organic extracts are dried(MgSO₄), filtered, and concentrated in vacuo affording the titlecompound (3.34 g) as a light colored liquid. ESMS:MH⁺ 215.4

Example 44 Preparation of 5-phenyl-2-(3-phenyl-propyl)-pentanoic acid(1-tert-butoxycarbonyl-aminomethylpiperidin-yl)-amide (52)

[0248]

[0249] 1-Butoxycarbonyl-4-aminomethylpiperidine (51) (0.30 g; 1.4 mmol)is dissolved in DMF (10 mL) at ambient temperature.5-Phenyl-2-(3-phenyl-propyl)-pentanoic acid (22) (0.415 g: 1.4 mmol) isadded followed sequentially by 1-hydroxybenzotriazole (0.2364 g; 1.75mmol), triethylamine (0.2439 mL; 1.75 mmol), andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.2952 g;1.54 mmol). The mixture is stirred at ambient temperature for 18 hoursthen poured onto ethyl acetate (300 mL) and extracted sequentially withwater (100 mL), 1N HCl (50 mL), saturated NaHCO₃ (50 mL), and brine (50mL). The organic layer is dried (MgSO₄), filtered, and concentrated invacuo. The residue is purified via silica gel chromatography withgradient elution (10%→50% ethyl acetate in hexanes) affording thedesired compound (0.67 g) as a colorless oil. ESMS:MH⁺ 493.4

Example 45 Preparation of 5-phenyl-2-(3-phenyl-propyl)-pentanoic acidaminomethyl-piperidin-4-ylamide (53)

[0250]

[0251] 5-Phenyl-2-(3-phenyl-propyl)-pentanoic acid(1-tert-butoxycarbonyl-aminomethylpiperidin-yl)-amide (52) (0.67 g; 1.36mmol) is dissolved in methylene chloride (25 mL) at ambient temperature.Trifluoroacetic acid (25 mL) is added in a slow stream, and the solutionis stirred for 90 minutes at ambient temperature. The solution isconcentrated in vacuo at 40° C. The residue is slurried in a mixture ofmethylene chloride (10 mL) and water (100 mL), then potassium carbonateis added until the slurry is alkaline. The slurry is diluted with water(200 mL) then extracted with methylene chloride (3×100 mL). The organicextracts are dried over MgSO₄, filtered, and concentrated in vacuoaffording the desired product (0.46 g) as a white solid.

Example 46 Preparation of 5-phenyl-2-(3-phenyl-propyl)-pentanoic acid{1-[2-hydroxy-3-quinolin-5-yloxy)-propyl]aminomethyl-piperidin-4-ylamide(54)

[0252]

[0253] 5-Phenyl-2-(3-phenyl-propyl)-pentanoic acidaminomethyl-piperidin-4-ylamide (53) (147.5 mg; 0.376 mmol) is dissolvedin isopropanol (10 mL) at ambient temperature.(R)-5-Oxiranylmethoxy-quinoline (2) (76.2 mg; 0.376 mmol) is added, thenthe mixture is heated to 70° C. and maintained for 18 hours. Aftercooling to ambient temperature, the solution is concentrated in vacuo at40° C. The residue is purified via silica gel chromatography withgradient elution (0%→20% methanol in methlene chloride) affording thedesired product (176.2 mg) as a light colored solid. ESMS:MH⁺ 594.4(base).

Example 47 Preparation of1-tert-butoxycarbonyl-4-carboxymethylpiperidine (55)

[0254]

[0255] 4-Pyridylacetic acid hydrochloride (2.5 g; 14.4 mmol) isdissolved in deionized water (30 mL) in a hydrogenation flask. PtO₂ (0.2g) is added and the mixture is hydrogenated at 50 psi for 18 hours atambient temperature. The solids are separated by decantation, and theaqueous solution is basicified with Na₂CO₃ (3 g). Dioxane (10 mL) isadded and the mixture is stirred rapidly at ambient temperature. Asolution of di-tert-butyl dicarbonate (9.44 g; 43.3 mmol) in dioxane (20mL) is added dropwise. The resulting mixture is stirred for 18 hoursthen concentrated in vacuo at 40° C. The resulting aqueous solution ispoured onto a solution of water (300 mL) and saturated aqueous NaHCO₃(10 mL), then the mixture is extracted with ethyl acetate (3×50 mL). Theaqueous layer is acidified with citric acid then extracted with ethylacetate (3×100 mL), dried (MgSO₄), filtered, and concentrated in vacuoaffording the desired product (3.60 g) as a solid. ESMS:MH⁺ 244.4

Example 48 Preparation of4-[4-phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-methylpiperidine-1-carboxylicacid tert-butyl ester (56)

[0256]

[0257]4-[4-Phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-methylpiperidine-1-carboxylicacid tert-butyl ester (55) (1 g; 4.11 mmol) is dissolved in DMF (30 mL)at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1)(1.25 g; 4.11 mmol), 1-Hydroxybenzotriazole (0.694 g; 5.14 mmol),triethylamine (0.716; 5.14 mmol), andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.87 g;4.54 mmol) are added sequentially. The mixture is stirred for 18 hoursat ambient temperature then poured onto ethyl acetate (300 mL) andextracted sequentially with water (100 mL), IN HCl (50 mL), saturatedNaHCO₃ (50 mL), and brine (50 mL). The organic layer is dried (MgSO₄),filtered, and concentrated in vacuo. The residue is purified via silicagel chromatography with gradient elution (10%→50% ethyl acetate inhexanes) affording the desired compound (1.62 g) as a colorless oil.ESMS:MH⁺ 493.6

Example 49 Preparation of methylpiperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (57)

[0258]

[0259]4-[4-Phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-methylpiperidine-1-carboxylicacid tert-butyl ester (56) (1.62 g; 3.29 mmol) is dissolved in methylenechloride (50 mL) at ambient temperature. Trifluoroacetic acid (50 mL) isadded in a slow stream, and the solution is stirred for 90 minutes atambient temperature. The solution is concentrated in vacuo at 40° C. Theresidue is slurried in a mixture of methylene chloride (30 mL) and water(200 mL), then potassium carbonate is added until the slurry isalkaline. The slurry is diluted with water (200 mL) then extracted withmethylene chloride (3×100 mL). The organic extracts are dried overMgSO₄, filtered, and concentrated in vacuo affording the desired product(1.23 g) as a white solid.

Example 50 Preparation of(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]methylpiperidine-4-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (58)

[0260]

[0261] Methylpiperidine-4-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (57) (150 mg; 0.382 mmol) isdissolved in isopropanol (10 mL) at ambient temperature.(R)-5-Oxiranylmethoxy-quinoline (2) (77.5 mg; 0.382 mmol) is added, thenthe mixture is heated to 70° C. and maintained for 18 hours. Aftercooling to ambient temperature, the solution is concentrated in vacuo at40° C. The residue is purified via silica gel chromatography withgradient elution (0%→25% methanol in methylene chloride) affording thedesired product (187.4 mg) as a solid foam. ESMS:MH⁺ 594.4 (base).

Example 51 Preparation of4-[4-(3-pyridyl)-1-(3-pyridyl-propyl)-butylcarbamoyl]-piperidine-1-carboxylicacid tert-butyl ester (59):

[0262]

[0263] 1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (0.5 g; 2.18mmol) is dissolved in DMF (10 mL) at ambient temperature.1-Hydroxybenzotriazole (0.37, 2.74 mmol), triethylamine (0.46 mL, 3.3mmol), 1,7-di-(3-pyridyl)-heptan-4-ol (0.59 g; 2.4 mmol) as preparedaccording to WO 98/20893 A1 assigned to Vertex Pharmaceuticals, andN-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (0.46 g;2.4 mmol) are added sequentially. The mixture is stirred at ambienttemperature for 18 hours. The mixture is then poured onto ethyl acetate(150 mL) and washed successively with water (50 mL), saturated aqueoussodium bicarbonate (10 mL), and brine (30 mL). The organic layer isdried over MgSO₄, filtered, and concentrated in vacuo. The residue ispurified via silica gel chromatography with gradient elution (0%→25%methanol in methylene chloride) affording the desired product (0.3754 g)as a yellow solid. ESMS:MH⁺ 482.4.

Example 52 Preparation of piperidine-4-carboxylic acid[4-(3pyridyl)-1-(3-pyridyl-propyl)-butyl]-amide (60):

[0264]

[0265]4-[4-(3-Pyridyl)-1-(3-pyridyl-propyl)-butylcarbamoyl]-piperidine-1-carboxylicacid tert-butyl ester (59) (0.3754 g; 0.78 mmol) is dissolved inmethylene chloride (6 mL) at ambient temperature. Trifluoroacetic acid(6 mL) is added in a slow stream, and the solution is stirred for 90minutes at ambient temperature. The solution is concentrated in vacuo at40° C. The residue is slurried in a mixture of methylene chloride (10mL) and water (50 mL), then potassium carbonate is added until theslurry is alkaline. The slurry is diluted with water (50 mL) thenextracted with methylene chloride (3×10 mL). The organic extracts aredried over MgSO₄, filtered, and concentrated in vacuo affording thedesired product (0.1704 g) as a yellow oil. ESMS:MH⁺ 382.4 (base).

Example 53 Preparation of(R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-4-carboxylicacid [4-(3-pyridyl-1-(3-pyridyl-propyl)-butyl]-amide (61)

[0266]

[0267] Piperidine-4-carboxylic acid[4-(3-pyridyl)-1-(3-pyridyl-propyl)-butyl]-amide (60) (170.4 mg; 0.45mmol) is dissolved in isopropanol (10 mL) at ambient temperature.(R)-5-Oxiranylmethoxy-quinoline (2) (90.0 mg; 0.45 mmol) is added, thenthe mixture is heated to 70° C. and maintained for 18 hours. Aftercooling to ambient temperature, the solution is concentrated in vacuo at40° C. The residue is purified via silica gel chromatography withgradient elution (0%→50% methanol in methylene chloride) affording thedesired product (120.2 mg) as an amber oil. ESMS:MH⁺ 583.4.

Example 54 Preparation of1-[(N-tert-butoxycarbonyl)-(N-methyl)-2-aminoacetyl]-piperidine-4-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (62)

[0268]

[0269] Piperidine-4-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (1.00 g; 2.64 mmol) isdissolved in methylene chloride (25 mL) at ambient temperature.(N-tert-butoxycarbonyl)-(N-methyl)-2-aminoacetic acid (0.60 g; 3.17mmol), N,N-diisopropylethylamine (0.75 g; 5.81 mmol) and PyBOP (1.65 g;3.17 mmol) are added sequentially. The reaction is stirred for 18 hoursat room temperature, then concentrated under reduced pressure. Theresidue is purified via silica gel chromatography (60%→90% ethyl acetatein hexanes) affording the desired product (62) as a solid. ESMS:MH⁺ 550

Example 55 Preparation of1-[(N-methyl)-2-aminoacetyl]-piperidine-4-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (63)

[0270]

[0271]1-[(N-tert-butoxycarbonyl)-(N-methyl)-2-aminoacetyl]-piperidine-4-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (62) (1.60 g; 2.91 mmol)is dissolved in methylene chloride (30 mL) at ambient temperature.Trifluoroacetic acid (15 mL) is added in a slow stream, and the solutionis stirred for 4 hours at ambient temperature. The solution isconcentrated in vacuo at 40° C. The residue is dissolved in methylenechloride (200 mL) and poured onto saturated sodium bicarbonate solution.The pH is adjusted to 9 with saturated potassium carbonate solution. Themixture is shaken the layers separated. The water layer is extractedwith methylene chloride (3×50 mL). The combined organic extracts arewashed with water, dried over MgSO₄, filtered, and concentrated in vacuoaffording the desired product (0.98 g) as a white solid.

Example 56 Preparation of1-{N-[2-(R)-hydroxy-3-(quinolin-5-yloxy)-propyl](N-methyl)-2aminoacetyl}-piperidine-4-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (64)

[0272]

[0273] 1-[(N-methyl)-2-aminoacetyl]-piperidine-4-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (63) (223.5 mg; 0.497 mmol])is dissolved in ethanol (10 mL) at ambient temperature.(R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added,then the mixture is refluxed for 17.5 hours. After cooling to ambienttemperature, the solution is concentrated in vacuo at 40° C. The residueis purified via silica gel chromatography with gradient elution(50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affordingthe desired product (110 mg) as a white solid. ESMS:MH⁺ 651.6.

Example 57 Preparation of N-tert-butoxycarbonyl-N-methyl-2-aminoaceticacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (65)

[0274]

[0275] (N-tert-butoxycarbonyl)-(N-methyl)-2-aminoacetic acid (1.00 g;5.29 mmol) is dissolved in methylene chloride (40 mL) at ambienttemperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (1.93 g; 6.34mmol), N,N-diisopropylethylamine (2.19 g; 16.9 mmol) and PyBOP (3.30 g;3.30 mmol) are added sequentially. The reaction is stirred for 1 hour atroom temperature, then concentrated under reduced pressure. The residueis purified via silica gel chromatography (20%→40% ethyl acetate inhexanes) affording the desired product (65) as a solid. CIMS:MH⁺ 439

Example 58 Preparation of N-methyl-2-aminoacetic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (66)

[0276]

[0277] N-tert-Butoxycarbonyl-N-methyl-2-aminoacetic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (65) (2.19 g; 4.99 mmol) isdissolved in methylene chloride (30 mL) at ambient temperature.Trifluoroacetic acid (20 mL) is added in a slow stream, and the solutionis stirred for 2.5 hours at ambient temperature. The solution isconcentrated in vacuo at 40° C. The residue is dissolved in methylenechloride (200 mL) and poured onto saturated sodium bicarbonate solution.The pH is adjusted to 9 with saturated potassium carbonate solution. Themixture is shaken the layers separated. The water layer is extractedwith methylene chloride (3×50 mL). The combined organic extracts arewashed with water, dried over MgSO₄, filtered, and concentrated in vacuoaffording the desired product (1.65 g) as a white solid. CIMS:MH⁺ 339

Example 59 Preparation ofN-(N-tert-butoxycarbonyl-piperidine-4-carbonyl)-(N-methyl)-2-aminoaceticacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (67)

[0278]

[0279] 1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (0.61 g; 2.66mmol) is dissolved in methylene chloride (20 mL) at ambient temperature.N-methyl-2-aminoacetic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide(66) (0.75 g; 2.22 mmol), N,N-diisopropylethylamine (0.63 g; 4.87 mmol)and PyBOP (1.38 g; 2.66 mmol) are added sequentially. The reaction isstirred for 14 hours at room temperature, then concentrated underreduced pressure. The residue is purified via silica gel chromatography(60%→80% ethyl acetate in hexanes) affording the desired product (67) asa clear oil. CIMS:MH⁺ 550

Example 60 Preparation ofN-(piperidine-4-carbonyl)-(N-methyl)-2-aminoacetic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (68)

[0280]

[0281]N-(N-tert-Butoxycarbonyl-piperidine-4-carbonyl)-(N-methyl)-2-aminoaceticacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (67) (1.46 g; 2.66 mmol)is dissolved in methylene chloride (30 mL) at ambient temperature.Trifluoroacetic acid (15 mL) is added in a slow stream, and the solutionis stirred for 2 hours at ambient temperature. The solution isconcentrated in vacuo at 40° C. The residue is dissolved in methylenechloride (200 mL) and poured onto saturated sodium bicarbonate solution.The pH is adjusted to 9 with saturated potassium carbonate solution. Themixture is shaken the layers separated. The water layer is extractedwith methylene chloride (3×50 mL). The combined organic extracts arewashed with water, dried over MgSO₄, filtered, and concentrated in vacuoaffording the desired product (1.65 g) as a clear oil. ESMS:MH⁺ 450.2

Example 61 Preparation ofN-{1-[2-(R)-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-4-carbonyl}-(N-methyl)-2-aminoaceticacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (69)

[0282]

[0283] N-(Piperidine-4-carbonyl)-(N-methyl)-2-aminoacetic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (68) (223.5 mg; 0.497 mmol)is dissolved in ethanol (12 mL) at ambient temperature.(R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added,then the mixture is refluxed for 15.5 hours. After cooling to ambienttemperature, the solution is concentrated in vacuo at 40° C. The residueis purified via silica gel chromatography with gradient elution(50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affordingthe desired product (110 mg) as a white solid. ESMS:MH⁺ 651.6

Example 62 Preparation of1-(1-tert-butoxycarbonylpiperidine-4-carbonyl)-piperidine-4-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl]amide (70)

[0284]

[0285] Piperidine-4-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (1.00 g; 2.64 mmol) isdissolved in methylene chloride (25 mL) at ambient temperature.1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (0.73 g; 3.17 mmol),N,N-diisopropylethylamine (0.75 g; 5.81 mmol) and PyBOP (1.65 g; 3.17mmol) are added sequentially. The reaction is stirred for 16 hours atroom temperature, then concentrated under reduced pressure. The residueis purified via silica gel chromatography (70%→90% ethyl acetate inhexanes) affording the desired product (70) as a solid. ESMS:MH⁺ 590.6

Example 63 Preparation of1-(piperidine-4-carbonyl)-piperidine-4-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (71)

[0286]

[0287]1-(1-tert-butoxycarbonylpiperidine-4-carbonyl)-piperidine-4-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (70) (1.84 g; 3.12 mmol)is dissolved in methylene chloride (30 mL) at ambient temperature.Trifluoroacetic acid (15 mL) is added in a slow stream, and the solutionis stirred for 1.25 hours at ambient temperature. The solution isconcentrated in vacuo at 40° C. The residue is dissolved in methylenechloride (200 mL) and poured onto saturated sodium bicarbonate solution.The pH is adjusted to 9 with saturated potassium carbonate solution. Themixture is shaken the layers separated. The water layer is extractedwith methylene chloride (3×50 mL). The combined organic extracts arewashed with water, dried over MgSO₄, filtered, and concentrated in vacuoaffording the desired product (1.65 g) as a white solid. ESMS:MH⁺ 490.4

Example 64 Preparation ofN-{1-[2-(R)-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-4-carbonyl}-piperidine-4-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (72)

[0288]

[0289] 1-(Piperidine-4-carbonyl)-piperidine-4-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (71) (243.4 mg; 0.497 mmol)is dissolved in ethanol (12 mL) at ambient temperature.(R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added,then the mixture is refluxed for 16 hours. After cooling to ambienttemperature, the solution is concentrated in vacuo at 40° C. The residueis purified via silica gel chromatography with gradient elution(50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affordingthe desired product (200 mg) as a white solid. ESMS:MH⁺ 691.6

Example 65 Preparation of2-[4-phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-piperidine-1-carboxylicacid tert-butyl ester (73):

[0290]

[0291] 1-tert-Butoxycarbonyl-piperidine-2-carboxylic acid (3 g; 13.1mmol) is dissolved in methylene chloride (100 mL) at ambienttemperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (4.77 g; 15.7mmol), diisopropylethylamine (7.3 mL; 41.9 mmol), and PyBOP (8.17 g;15.7 mmol) are added sequentially. The mixture is stirred for 17 hoursat ambient temperature then concentrated in vacuo at 40° C. The residueis purified via silica gel chromatography with gradient elution (10%→30%ethyl acetate in hexanes) affording the desired product as an oil.ESMS:MH⁺ 479.4

Example 66 Preparation of2-[4-phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-piperidine (74):

[0292]

[0293]2-[4-Phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-piperidine-1-carboxylicacid tert-butyl ester (73) (6.77 g; 14.1 mmol) is dissolved in methylenechloride (60 mL) at ambient temperature. Trifluoroacetic acid (40 mL) isadded in a slow stream, and the solution is stirred for 1.25 hours atambient temperature. The solution is concentrated in vacuo at 40° C. Theresidue is dissolved in methylene chloride (300 mL) and poured ontosaturated sodium bicarbonate solution. The pH is adjusted to 9 withsaturated potassium carbonate solution. The mixture is shaken the layersseparated. The water layer is extracted with methylene chloride (3×100mL). The combined organic extracts are washed with water, dried overMgSO₄, filtered, and concentrated in vacuo affording the desired product(5.34 g) as a white solid. ESMS:MH⁺ 379.2

Example 67 Preparation of1-(1-tert-butoxycarbonylpiperidine-4-carbonyl)-piperidine-2-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (75)

[0294]

[0295] Piperidine-2-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (74) (1.00 g; 2.64 mmol) isdissolved in methylene chloride (25 mL) at ambient temperature. 1-tert-Butoxycarbonyl-piperidine4-carboxylic acid (0.73 g; 3.17 mmol),N,N-diisopropylethylamine (0.75 g; 5.81 mmol) and PyBOP (1.65 g; 3.17mmol) are added sequentially. The reaction is stirred for 16 hours atroom temperature, then concentrated under reduced pressure. The residueis purified via silica gel chromatography (30%→50% ethyl acetate inhexanes) affording the desired product (75) as a solid. ESMS:MH⁺ 590.6

Example 68 Preparation of1-(piperidine-4-carbonyl)-piperidine-2-carboxylic acid[4-phenyl-1(3-phenyl-propyl)-butyl]-amide (76)

[0296]

[0297]1-(1-tert-butoxycarbonylpiperidine-4-carbonyl)-piperidine-2-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (75) (1.41 g; 2.39 mmol)is dissolved in methylene chloride (30 mL) at ambient temperature.Trifluoroacetic acid (15 mL) is added in a slow stream, and the solutionis stirred for 2.25 hours at ambient temperature. The solution isconcentrated in vacuo at 40° C. The residue is dissolved in methylenechloride (200 mL) and poured onto saturated sodium bicarbonate solution.The pH is adjusted to 9 with saturated potassium carbonate solution. Themixture is shaken the layers separated. The water layer is extractedwith methylene chloride (3×50 mL). The combined organic extracts arewashed with water, dried over MgSO₄, filtered, and concentrated in vacuoaffording the desired product (1.02 g) as an oil. ESMS: MH⁺ 490.4

Example 69 Preparation of N-{b1-[2-(R)-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-4-carbonyl}-piperidine-2-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl]amide (77)

[0298]

[0299] 1-(Piperidine-4-carbonyl)-piperidine-2-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (76) (243.4 mg; 0.497 mmol)is dissolved in ethanol (12 mL) at ambient temperature.(R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added,then the mixture is refluxed for 17 hours. After cooling to ambienttemperature, the solution is concentrated in vacuo at 40° C. The residueis purified via silica gel chromatography with gradient elution(50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affordingthe desired product (250 mg) as a white solid. ESMS:MH⁺ 691.6

Example 70 Preparation of1-(1-tert-butoxycarbonylpiperidine-3-carbonyl)-piperidine-3-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (78)

[0300]

[0301] Piperidine-3-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (13) (1.00 g; 2.64 mmol) isdissolved in methylene chloride (25 mL) at ambient temperature.1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (0.73 g; 3.17 mmol),N,N-diisopropylethylamine (0.75 g; 5.81 mmol) and PyBOP (1.65 g; 3.17mmol) are added sequentially. The reaction is stirred for 18 hr. at roomtemperature, then concentrated under reduced pressure. The residue ispurified via silica gel chromatography (50%→70% ethyl acetate inhexanes) affording the desired product (78) as a solid. ESMS:MH⁺ 590.6

Example 71 Preparation of1-(piperidine-3-carbonyl)-piperidine-3-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (79)

[0302]

[0303]1-(1-tert-butoxycarbonylpiperidine-3-carbonyl)-piperidine-3-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (78) (1.41 g; 2.39 mmol)is dissolved in methylene chloride (40 mL) at ambient temperature.Trifluoroacetic acid (20 mL) is added in a slow stream, and the solutionis stirred for 5 hours at ambient temperature. The solution isconcentrated in vacuo at 40° C. The residue is dissolved in methylenechloride (200 mL) and poured onto saturated sodium bicarbonate solution.The pH is adjusted to 9 with saturated potassium carbonate solution. Themixture is shaken the layers separated. The water layer is extractedwith methylene chloride (3×50 mL). The combined organic extracts arewashed with water, dried over MgSO₄, filtered, and concentrated in vacuoaffording the desired product (0.97 g) as a white solid.

Example 72 Preparation ofN-{1-[2-(R)-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-3carbonyl}-piperidine-3-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (80)

[0304]

[0305] 1-(Piperidine-3-carbonyl)-piperidine-3-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (79) (243.4 mg; 0.497 mmol)is dissolved in ethanol (12 mL) at ambient temperature.(R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added,then the mixture is refluxed for 17 hours. After cooling to ambienttemperature, the solution is concentrated in vacuo at 40° C. The residueis purified via silica gel chromatography with gradient elution(50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affordingthe desired product (230 mg) as a white solid. ESMS:MH⁺ 691.6

Example 73 Preparation of1-(1-tert-butoxycarbonylpiperidine-3-carbonyl)-piperidine-2-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (81)

[0306]

[0307] Piperidine-2-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (74) (1.00 g; 2.64 mmol) isdissolved in methylene chloride (25 mL) at ambient temperature.1-tert-Butoxycarbonyl-piperidine-3-carboxylic acid (0.73 g; 3.17 mmol),N,N-diisopropylethylamine (0.75 g; 5.81 mmol) and PyBOP (1.65 g; 3.17mmol) are added sequentially. The reaction is stirred for 19 hours atroom temperature, then concentrated under reduced pressure. The residueis purified via silica gel chromatography (30%→50% ethyl acetate inhexanes) affording the desired product (81) as a solid. ESMS:MH⁺ 590.6

Example 74 Preparation of1-(piperidine-3-carbonyl)-piperidine-2-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (82)

[0308]

[0309]1-(1-tert-butoxycarbonylpiperidine-3-carbonyl)-piperidine-2-carboxylicacid [4-phenyl-1(3-phenyl-propyl)-butyl]-amide (81) (1.35 g; 2.29 mmol)is dissolved in methylene chloride (40 mL) at ambient temperature.Trifluoroacetic acid (20 mL) is added in a slow stream, and the solutionis stirred for 4 hours at ambient temperature. The solution isconcentrated in vacuo at 40° C. The residue is dissolved in methylenechloride (200 mL) and poured onto saturated sodium bicarbonate solution.The pH is adjusted to 9 with saturated potassium carbonate solution. Themixture is shaken the layers separated. The water layer is extractedwith methylene chloride (3×50 mL). The combined organic extracts arewashed with water, dried over MgSO₄, filtered, and concentrated in vacuoaffording the desired product (1.09 g) as an oil.

Example 75 Preparation ofN-{1-[2-(R)-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-2carbonyl}-piperidine-3-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (83)

[0310]

[0311] 1-(Piperidine-3-carbonyl)-piperidine-2-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (82) (243.4 mg; 0.497 mmol)is dissolved in ethanol (12 mL) at ambient temperature.(R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added,then the mixture is refluxed for 21 hours. After cooling to ambienttemperature, the solution is concentrated in vacuo at 40° C. The residueis purified via silica gel chromatography with gradient elution(50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affordingthe desired product (210 mg) as a white solid. ESMS:MH⁺ 691.2

Example 76 Preparation of N-tert-butoxycarbonyl-3-(3-pyridyl)-alanine[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (84)

[0312]

[0313] N-tert-Butoxycarbonyl-3-(3-pyridyl)-alanine (1.00 g; 3.76 mmol)is dissolved in methylene chloride (25 mL) at ambient temperature.1,7-Diphenyl-4-aminoheptane hydrochloride (1) (1.37 g; 4.51 mmol),N,N-diisopropylethylamine (1.55 g; 12.0 mmol) and PyBOP (2.34 g; 4.51mmol) are added sequentially. The reaction is stirred for 2.5 hours atroom temperature, then concentrated under reduced pressure. The residueis purified via silica gel chromatography (60%→80% ethyl acetate inhexanes) affording the desired product (84) as a solid. ESMS:MH⁺ 516.2

Example 77 Preparation of 3-(3-pyridyl)-alanine[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (85)

[0314]

[0315] N-tert-Butoxycarbonyl-3-(3-pyridyl)-alanine[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (84) (2.08 g; 4.03 mmol) isdissolved in methylene chloride (40 mL) at ambient temperature.Trifluoroacetic acid (20 mL) is added in a slow stream, and the solutionis stirred for 4 hours at ambient temperature. The solution isconcentrated in vacuo at 40° C. The residue is dissolved in methylenechloride (200 mL) and poured onto saturated sodium bicarbonate solution.The pH is adjusted to 9 with saturated potassium carbonate solution. Themixture is shaken the layers separated. The water layer is extractedwith methylene chloride (3×50 mL). The combined organic extracts arewashed with water, dried over MgSO₄, filtered, and concentrated in vacuoaffording the desired product (1.59 g) as an oil. ESMS:MH⁺ 416.2

Example 78 Preparation ofN-(N-tert-butoxycarbonyl-piperidine-4-carbonyl)-3-(3-pyridyl)-alanine[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (86)

[0316]

[0317] 1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (0.66 g; 2.89mmol) is dissolved in methylene chloride (25 mL) at ambient temperature.3-(3-Pyridyl)-alanine [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (85)(1.00 g; 2.41 mmol), N,N-diisopropylethylamine (0.68 g; 5.29 mmol) andPyBOP (1.50 g; 2.89 mmol) are added sequentially. The reaction isstirred for 5 hours at room temperature, then concentrated under reducedpressure. The residue is purified via silica gel chromatography(80%→100% ethyl acetate in hexanes) affording the desired product (86)as a white solid. ESMS:MH⁺ 627.6

Example 79 Preparation ofN-(piperidine-4-carbonyl)-3-(3-pyridyl)-alanine[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (87)

[0318]

[0319] N-(N-tert-Butoxycarbonyl-piperidine-4-carbonyl)-3-(3-pyridyl)-alanine [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (86)(1.30 g; 2.07 mmol) is dissolved in methylene chloride (40 mL) atambient temperature. Trifluoroacetic acid (20 mL) is added in a slowstream, and the solution is stirred for 2 hours at ambient temperature.The solution is concentrated in vacuo at 40° C. The residue is dissolvedin methylene chloride (200 mL) and poured onto saturated sodiumbicarbonate solution. The pH is adjusted to 9 with saturated potassiumcarbonate solution. The mixture is shaken the layers separated. Thewater layer is extracted with methylene chloride (3×50 mL). The combinedorganic extracts are washed with water, dried over MgSO₄, filtered, andconcentrated in vacuo affording the desired product (0.98 g) as a whitesolid. ESMS:MH⁺ 527.2

Example 80 Preparation ofN-{1-[2-(R)-hydroxy-3-(quinolin-5-yloxy)-propyl]piperidine-4-carbonyl}-3-(3-pyridyl)-alanine [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (88)

[0320]

[0321] N-(Piperidine-4-carbonyl)-3-(3-pyridyl)-alanine [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (87) (261.8 mg; 0.497 mmol) isdissolved in ethanol (12 mL) at ambient temperature.(R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added,then the mixture is refluxed for 25 hours. After cooling to ambienttemperature, the solution is concentrated in vacuo at 40° C. The residueis purified via silica gel chromatography with gradient elution(50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affordingthe desired product (190 mg) as a white solid. ESMS:MH⁺ 728.6

Example 81 Preparation of (R)-6-oxiranylmethoxy-guinoline (89)

[0322]

[0323] Sodium hydride (60 weight %; 0.36 g; 9.0 mmol) is washed withhexanes (3×5 mL) under an argon blanket. DMF (3 mL) is then added atambient temperature and the stirred slurry is cooled to 5° C. A solutionof 6-hydroxyquinoline (1.00 g; 6.9 mmol) in DMF (13 mL) is addeddropwise over 10 minutes. The resulting mixture is allowed to warm toambient temperature over 30 minutes affording a clear, reddish-brownsolution. A solution of (R)-(−)-glycidyl tosylate (2.04 g; 9.0 mmol) inDMF (10 mL) is added dropwise over 10 minutes. The resulting mixture isstirred at ambient temperature for 13 hours, quenched by the addition ofsaturated aqueous ammonium chloride (5 mL), poured onto water (150 mL),and extracted with ether (3×75 mL). The combined ether layers are washedwith saturated aqueous sodium bicarbonate (2×75 mL), then dried overMgSO₄, filtered, and concentrated in vacuo. The residue is purified viasilica gel chromatography with gradient elution (40%→70% ethyl acetatein hexanes) affording the desired product (0.94 g) as an oil. CIMS:MH⁺202.

Example 82 Preparation of(R)-1-[2-hydroxy-3-(quinolin-6-yloxy)-propyl]piperidine-4-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (90)

[0324]

[0325] Piperidine-4-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (100.0 mg; 0.264 mmol) isdissolved in ethanol (10 mL) at ambient temperature.(R)-6-Oxiranylmethoxy-quinoline (89) (53.0 mg; 0.264 mmol) is added,then the mixture is refluxed for 17 hours. After cooling to ambienttemperature, the solution is concentrated in vacuo at 40° C. The residueis purified via silica gel chromatography with gradient elution (70%→90%ethyl acetate in hexanes, then 50%→70% acetone in hexanes) affording thedesired product (50 mg) as a white solid. ESMS:MH⁺ 580.4.

Example 83 Preparation of (R)-4-oxiranylmethoxy-guinoline (91)

[0326]

[0327] Sodium hydride (60 weight %; 1.79 g; 44.8 mmol) is washed withhexanes (3×10 mL) under an argon blanket. DMF (17 mL) is then added atambient temperature and the stirred slurry is cooled to 5° C. A solutionof 5-hydroxyquinoline (5.00 g; 34.4 mmol) in DMF (65 mL) is addeddropwise over 10 minutes. The resulting mixture is allowed to warm toambient temperature over 1 hour affording a clear, reddish-brownsolution. A solution of (R)-(−)-glycidyl tosylate (10.22 g; 44.8 mmol)in DMF (50 mL) is added dropwise over 10 minutes. The resulting mixtureis stirred at ambient temperature for 20.5 hours, quenched by theaddition of saturated aqueous ammonium chloride (25 mL), poured ontowater (750 mL), and extracted with ether (3×375 mL). The combined etherlayers are washed with saturated aqueous sodium bicarbonate (2×375 mL),then dried over MgSO₄, filtered, and concentrated in vacuo. The residueis purified via silica gel chromatography with gradient elution (50%→60%acetone in hexanes) affording the desired product (1.11 g) as a tansolid. ESMS:MH⁺ 202.2.

Example 84 Preparation of(R)-1-[2-hydroxy-3-(quinolin-4-yloxy)-propyl]piperidine-4-carboxylicacid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (92)

[0328]

[0329] Piperidine-4-carboxylic acid[4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (70.3 mg; 0.186 mmol) isdissolved in ethanol (10 mL) at ambient temperature.(R)-4-Oxiranylmethoxy-quinoline (91) (37.4 mg; 0.186 mmol) is added,then the mixture is refluxed for 22 hours. After cooling to ambienttemperature, the solution is concentrated in vacuo at 40° C. The residueis purified via silica gel chromatography with gradient elution(50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affordingthe desired product (50 mg) as a yellow solid. ESMS: MH⁺580.4.

Example 85 Activity of the Compounds

[0330] Accumulation Index of various compounds prepared above was testedaccording to the method in Reference Example 3. The results are in Table3. Substrate Potential of various compounds prepared above was testedaccording to the method in Reference Example 4. The results are in Table3. TABLE 3 Accumulation Index and Substrate Potential of the ActiveCompounds Accumulation Substrate Potential Compound IndexKa_((MDR1−ATPase)), KI_((MDR1−ATPase+vetapamil)) Example 5 10 noactivation, 0.3 micromolar Example 6 6 Example 10 11 Example 11 11 noactivation, 0.02 micromolar Example 14 8 no activation, 0.3 micromolarExample 15 9 weak activation, >50 micromolar Example 16 8 Example 18 9Example 19 5 Example 21 8 Example 25 12 0.005 micromolar, 0.01micromolar Example 26 5 no activation, 0.5 micromolar Example 29 6Example 32 9 0.01 micromolar, 0.05 micromolar Example 33 8 Example 34 6Example 35 7 Example 36 9 no activation, 1 micromolar Example 39 13Example 40 12 Example 41 10 Example 42 12 Example 46 8 Example 50 10Example 53 8 Example 56 9 Example 61 7 Example 64 8 Example 69 9 Example72 9 Example 75 10 Example 80 9 Example 82 7 Example 84 9

Example 86 Oral Composition for the Active Compound of this Invention

[0331] A composition for oral administration is prepared by reducing anactive compound according to this invention to a No. 60 powder. Starchand magnesium stearate are passed through a No. 60 bolting cloth ontothe powder. The combined ingredients are mixed for 10 minutes and filledinto a hard shell capsule of a suitable size at a fill weight of 100 mgper capsule. The capsule contains the following composition: ActiveCompound 5 mg Starch 88 mg  Magnesium Stearate 7 mg

Example 87 Oral Composition for the Active Compound of this Inventionwith a Chemotherapeutic Agent

[0332] A mixture of vinblastine and an active compound according to thisinvention is reduced to a No. 60 powder. Lactose and magnesium stearateare passed through a No. 60 bolting cloth onto the powder. The combinedingredients are mixed for 10 minutes, and then filled into a No. 1 drygelatin capsule. Each capsule contains the following composition: ActiveCompound 5 mg Vinblastine 5 mg Lactose 580 mg  Magnesium Stearate 10 mg 

Example 88 Parenteral Composition for the Active Compound of thisInvention

[0333] An active compound according to this invention (1 mg) isdissolved in 1 mL of a solution of 10% cremaphor, 10% ethanol, and 80%water. The solution is sterilized by filtration.

Example 89 Parenteral Composition for the Active Compound of thisInvention

[0334] A sufficient amount of an active compound according to thisinvention and TAXOL® are dissolved in a 0.9% sodium chloride solutionsuch that the resulting mixture contains 0.9 mg/mL of the activecompound of this invention and 1.2 mg/mL TAXOL®.

[0335] A sufficient amount of the solution to deliver 135 mg/sq m TAXOL®is administered intravenously over 24 hours to a patient suffering fromovarian cancer.

What is claimed is:
 1. A compound having the structure:

or an optical isomer, diastereomer, enantiomer, orpharmaceutically-acceptable salt, or amide, ester, or imide susceptibleto being cleaved in vivo by a mammalian subject to yield the compound,wherein: (a) A¹ and A² are each, independently, selected from the groupconsisting of a hydrogen atom and a group having the structure:

 with the proviso that at A¹ and A² are not both hydrogen atoms, andwherein: (i) each R¹ is independently selected from the group consistingof a hydrogen atom, a hydroxyl group, a hydrocarbon group, a substitutedhydrocarbon group, a heterogeneous group, a substituted heterogeneousgroup, a carbocyclic group, a substituted carbocyclic group, aheterocyclic group, a substituted heterocyclic group, an aromatic group,a substituted aromatic group, a heteroaromatic group, and a substitutedheteroaromatic group; (ii) x is from 0 to about 10; (iii) R² is selectedfrom the group consisting of a hydrocarbon group, a substitutedhydrocarbon group, a heterogeneous group, a substituted heterogeneousgroup, a carbocyclic group, a substituted carbocyclic group, aheterocyclic group, a substituted heterocylclic group, an aromaticgroup, a substituted aromatic group, a heteroaromatic group, and asubstituted heteroaromatic group; (iv) D¹ and D² are each independentlyselected from the group consisting of —C(O)— and —NR³—; with the provisothat wherein when D¹ is —NR¹— then D² is —C(O)—, and wherein when D² is—NR³— then D¹ is —C(O)—; and (v) R³ is selected from the groupconsisting of a hydrogen atom and R²; and (b) A³ has the structure:

 wherein: (i) each R¹ is independently selected from the groupconsisting of a hydrogen atom, a hydroxyl group, a hydrocarbon group, asubstituted hydrocarbon group, a heterogeneous group, a substitutedheterogeneous group, a carbocyclic group, a substituted carbocyclicgroup, a heterocyclic group, a substituted heterocyclic group, anaromatic group, a substituted aromatic group, a heteroaromatic group,and a substituted heteroaromatic group; (ii) t is from 0 to about 6;(iii) D⁴ is selected from the group consisting of —C(O)— and —CH(R¹)—,(iv) D⁵ is selected from the group consisting of —NHR⁶ and —OR⁶, and (v)R⁶ is selected from the group consisting of a hydrocarbon group, asubstituted hydrocarbon group, a heterogeneous group, a substitutedheterogeneous group, a carbocyclic group, a substituted carbocyclicgroup, a heterocyclic group, a substituted heterocyclic group, anaromatic group, a substituted aromatic group, a heteroaromatic group,and a substituted heteroaromatic group, with the proviso that whereinwhen: +P4 (a) A⁴ is a heterocyclic group having 6 member atoms; and +P4(b) A¹ or A² is hydrogen; and (c) each R¹ is selected from the groupconsisting of a hydrogen atom, a hydroxyl group, a hydrocarbon group, asubstituted hydrocarbon group, a carbocyclic group, a substitutedcarbocyclic group, an aromatic group, and a substituted aromatic group;and (d) each R² is selected from the group consisting of a hydrocarbongroup, a substituted hydrocarbon group, a carbocyclic group, asubstituted carbocyclic group, an aromatic group, and a substitutedaromatic group; then R⁶ is not a quinolyl group; and (c) A⁴ is aheterocyclic group having from 4 to 9 member atoms.
 2. The compoundaccording to claim 1 wherein A⁴ is a heterocyclic group having 5 or 6member atoms.
 3. The compound according to claim 2 wherein x is 0 toabout
 1. 4. The compound according to claim 3 wherein at least one R¹ isselected from the group consisting of a hydrogen atom and a hydroxylgroup.
 5. The compound according to claim 4 wherein at least one R² isselected from the group consisting of a hydrocarbon group, a substitutedhydrocarbon group, a heterogeneous group, a substituted heterogeneousgroup, an aromatic group, a substituted aromatic group, a heteroaromaticgroup, and a substituted heteroaromatic group.
 6. The compound accordingto claim 5 wherein each R² is selected from the group consisting of:

wherein: (a) a is at least about 2; (b) b is at least about 2; (c) c isabout 1 to about 3; (d) d is about 1 to about 3; and each R¹² and R¹³are each independently selected from the group consisting of hydrocarbongroups and substituted hydrocarbon groups.
 7. The compound according toclaim 5 wherein D⁴is —C(O)— and t is
 0. 8. The compound according toclaim 5 wherein D⁴ is —C(O)— and D⁵is —O_(r)R⁶.
 9. The compoundaccording to claim 5 wherein D⁴ is —CH(R¹)— and D⁵ is —O_(r)R⁶.
 10. Thecompound according to claim 5 wherein D⁴ is —CH(R¹)— and D¹ is —NHR⁶.11. A composition comprising: (a) the compound according to claim 1; and(b) a pharmaceutically acceptable carrier.
 12. The composition accordingto claim 11 wherein the compound inhibits transport protein activity.13. A composition comprising: (a) the compound according to claim 5; and(b) a pharmaceutically acceptable carrier.
 14. The composition accordingto claim 13 wherein the compound inhibits transport protein activity.15. A method selected from the group consisting of treating multidrugresistance, inhibiting transport protein activity; and combinationsthereof, comprising administering to a mammal in need of such treatmentor inhibition the composition according to claim
 11. 16. A methodselected from the group consisting of treating multidrug resistance,inhibiting transport protein activity; and combinations thereof,comprising administering to a mammal in need of such treatment orinhibition the composition according to claim 13.